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WO2013186398A1 - Tfeb for use in treating obesity or metabolic syndrome - Google Patents

Tfeb for use in treating obesity or metabolic syndrome Download PDF

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Publication number
WO2013186398A1
WO2013186398A1 PCT/EP2013/062546 EP2013062546W WO2013186398A1 WO 2013186398 A1 WO2013186398 A1 WO 2013186398A1 EP 2013062546 W EP2013062546 W EP 2013062546W WO 2013186398 A1 WO2013186398 A1 WO 2013186398A1
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Prior art keywords
goterm
tfeb
regulation
bax
genes
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PCT/EP2013/062546
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French (fr)
Inventor
Andrea Ballabio
Carmine SETTEMBRE
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Fondazione Telethon
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0058—Nucleic acids adapted for tissue specific expression, e.g. having tissue specific promoters as part of a contruct

Definitions

  • the present invention relates to a vector comprising a TFEB coding sequence under the control of a promoter able to efficiently express said TFEB coding sequence for use in the treatment of obesity and/or metabolic syndrome, to a host cell comprising said vector, pharmaceutical compositions and uses thereof.
  • the liver plays a major role in the adaptation to starvation (7, 2).
  • the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy (3, 4), is activated by starvation and participates in a lysosomal nutrient-sensing mechanism (5).
  • TFEB transcription factor EB
  • HHL helix-loop-helix
  • LZ leucine zipper domains flanked by an upstream basic region
  • WO 2010/0921 12 relates to TFEB protein, synthetic or biotechnological functional derivative thereof, peptide fragments thereof, chimeric molecules comprising the TFEB protein, synthetic or biotechnological functional derivative thereof acting either directly or indirectly on a CLEAR element.
  • the document is silent concerning obesity or metabolic syndrome.
  • transgenic mice that specifically lack TFEB in the liver (Tcfeb- i KO ), a primary player in the starvation response.
  • TFEB regulates key genes involved in lipid breakdown which in the absence of TFEB failed to respond to starvation.
  • TFEB loss of function in the mouse liver resulted in an impaired lipid catabolism and ketogenesis.
  • TFEB delivery to the liver increased energy expenditure and lipid breakdown and rescued the metabolic syndrome in both diet- and genetically-induced obese mice.
  • This regulatory mechanism which may have evolved to coordinate the adaptation to food deprivation, is a promising therapeutic target for disorders of lipid metabolism.
  • a vector comprising a TFEB coding sequence, or a functional or allelic variant or derivative or fragment thereof, under the control of a promoter able to efficiently express said TFEB coding sequence for use in the treatment of obesity and/or metabolic syndrome.
  • the treatment is by gene therapy.
  • the above TFEB functional variant can be a TFEB mutant, e.g. TFEB(S142A) and TFEB(S211 A) mutant.
  • the vector according the invention is preferably a viral vector, more preferably selected from the group consisting of: adenoviral vectors, lentiviral vectors, retroviral vectors, adeno associated vectors (AAV) or naked plasmid DNA vectors, even more preferably belonging to the group of: helper-dependent adenoviral vectors.
  • adenoviral vectors preferably selected from the group consisting of: adenoviral vectors, lentiviral vectors, retroviral vectors, adeno associated vectors (AAV) or naked plasmid DNA vectors, even more preferably belonging to the group of: helper-dependent adenoviral vectors.
  • AAV adeno associated vectors
  • the vector according the invention preferably comprises a liver specific promoter and/or regulatory sequences.
  • Said liver specific promoter is preferably a phosphoenolpyruvate carboxykinase (PEPCK) promoter having essentially the sequence of SEQ ID No. 2.
  • Said liver regulative sequence is preferably the liver specific enhancer Locus Control Region (LCR) from the apoE locus having essentially the sequence of SEQ ID No. 3.
  • LCR liver specific enhancer Locus Control Region
  • the above vector comprises a construct having essentially the sequence of SEQ ID No.4.
  • the vector of the invention enhances lipid breakdown.
  • composition comprising the vector of the invention or the host cell of the invention or the viral particle of the invention for use in the treatment of obesity and/or metabolic syndrome.
  • Another object of the invention is a method of treatment of obesity and/or metabolic syndrome of a subject in need thereof, said method comprising administering an effective amount of the pharmaceutical composition as above described.
  • a further object of the invention is TFEB coding sequence, protein or a functional or allelic variant thereof for use in the treatment of an obesity and/or metabolic syndrome.
  • Another object of the invention is a method of treatment of obesity and/or metabolic syndrome comprising administering a therapeutically effective amount of TFEB coding sequence, protein or a functional or allelic variant thereof or of a suitable amount of a pharmaceutical composition comprising TFEB coding sequence, protein or a functional or allelic variant thereof to a patient in need thereof.
  • a further object is a method for enhancing lipid breakdown comprising the administration of TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof.
  • the administration of TFEB is made by gene therapy or by the administration of a pharmaceutical composition comprising TFEB coding sequence, protein or a functional or allelic variant thereof.
  • the TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof preferably enhances free fatty acid (FFA) catabolism and ketogenesis and/or regulates genes expression by up-regulating genes related to lipid breakdown and/or down-regulating genes related to lipid biosynthesis and/or in inflammatory response.
  • FFA free fatty acid
  • TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof preferably acts through the binding to said genes promoters and/or the up-regulated gene is PGCla and/or PPARa.
  • the therapy is a gene therapy.
  • a synthetic or biotechnological functional derivative of a protein, peptide fragments of a protein, chimeric molecules comprising the TFEB protein, synthetic or biotechnological functional derivative thereof are defined as molecules able to maintain the therapeutic effect of TFEB, i.e the treatment of obesity and/or metabolic syndrome.
  • a functional derivative of TFEB may be a sequence comprising the sequence of TFEB and the sequence of an extra non endogenous nuclear localization signal.
  • compositions comprising: a) an effective amount of a vector as described herein or an effective amount of a transformed host cell as described herein, and b) a pharmaceutically acceptable carrier, which may be inert or physiologically active.
  • pharmaceutically-acceptable carriers includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, and the like that are physiologically compatible.
  • suitable carriers, diluents and/or excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combination thereof.
  • isotonic agents such as sugars, polyalcohols, or sodium chloride in the composition.
  • suitable carrier include: (1) Dulbecco's phosphate buffered saline, pH ⁇ 7.4, containing or not containing about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v sodium chloride (NaCl)), and (3) 5% (w/v) dextrose; and may also contain an antioxidant such as tryptamine and a stabilizing agent such as Tween 20.
  • compositions encompassed by the present invention may also contain a further therapeutic agent for the treatment of obesity and/or metabolic syndrome.
  • compositions of the invention may be in a variety of forms. These include for example liquid, semi-solid, but the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions.
  • the preferred mode of administration is parenteral (e.g. intravenous, intramuscular, intraperinoneal, subcutaneous).
  • the compositions of the invention are administered intravenously as a bolus or by continuous infusion over a period of time.
  • they are injected by intramuscular, subcutaneous, intraarticular, intrasynovial, intratumoral, peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects.
  • Sterile compositions for parenteral administration can be prepared by incorporating the vector or host cell as described in the present invention in the required amount in the appropriate solvent, followed by sterilization by micro filtration.
  • solvent or vehicle there may be used water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combination thereof.
  • isotonic agents such as sugars, polyalcohols, or sodium chloride in the composition.
  • These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents.
  • Sterile compositions for parenteral administration may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.
  • compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
  • doses depend on the desired effect, the duration of the treatment and the route of administration used and may be determined easily by the skilled person in the art using known methods. As well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
  • a metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. Some studies have shown the prevalence in the USA to be an estimated 25% of the population, and prevalence increases with age. Metabolic syndrome is also known as metabolic syndrome X, cardiometabolic syndrome, syndrome X, insulin resistance syndrome, Reaven's syndrome (named for Gerald Reaven), and CHAOS (in Australia).
  • Raised triglycerides > 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality;
  • HDL high-density lipoprotein
  • Raised blood pressure systolic BP > 130 or diastolic BP >85 mm Hg, or treatment of previously diagnosed hypertension;
  • Raised fasting plasma glucose >100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes.
  • the World Health Organization 1999 criteria require the presence of any one of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, and two of the following:
  • ⁇ Blood pressure > 140/90 mmHg; •
  • Dyslipidemia triglycerides (TG): > 1.695 mmol/L and HDL cholesterol (HDL-C) ⁇ 0.9 mmol/L (male), ⁇ 1.0 mmol/L (female);
  • Microalbuminuria urinary albumin excretion ratio > 20 ⁇ g/min or albumin: creatinine ratio > 30 mg/g.
  • Dyslipidemia HDL-C ⁇ 40 mg/dL (male), ⁇ 50 mg/dL (female);
  • lipid breakdown by enhancing lipid breakdown it is meant that at least one of the following pathway related to lipid breakdown is positively regulated by the molecules of the present invention: glycerolipid catabolism, fatty acid binding and transport, lipid and fatty acid catabolism, membrane lipid catabolism, fatty acid oxidation, isoprenoid catabolism, steroid catabolism, sphingolipid catabolism, negative regulation of lipid biosynthetic process.
  • enhancing free fatty acid (FFA) catabolism and ketogenesis is defined considering that free fatty acids (FFA) are non-esterified fatty acid, released by the hydrolysis of triglycerides within adipose tissue. Free fatty acids can be used as an immediate source of energy by many organs and can be converted by the liver into ketone bodies.
  • Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, in the end generating acetyl-CoA, the entry molecule for the citric acid cycle, the main energy supply of animals. It includes three major steps:
  • lipolysis The breakdown of fatty acids is known as lipolysis.
  • the products of lipolysis, free fatty acids, are released into the bloodstream and circulate throughout the body.
  • Fatty acids must be activated before they can be carried into the mitochondria, where fatty acid oxidation occurs. This process occurs in two steps catalyzed by the enzyme fatty acyl-CoA synthetase.
  • the inner mitochondrial membrane is impermeable to fatty acids and a specialized carnitine carrier system operates to transport activated fatty acids from cytosol to mitochondria.
  • the final product is acetyl- CoA, the entry molecule for the citric acid cycle.
  • Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown. Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis physiologically occurs in response to unavailability of blood glucose. This is caused by low glucose levels in the blood, after exhaustion of cellular carbohydrate stores, such as glycogen or, synthesis of ketones can occur due to excessively high levels of blood glucose that are unable to be stored as glycogen in liver and muscle. The production of ketone bodies is then initiated to make available energy that is stored as fatty acids. Fatty acids are enzymatically broken down in ⁇ -oxidation to form acetyl-CoA.
  • acetyl-CoA is further oxidized and its energy transferred as electrons to NADH, FADH2, and ATP in the citric acid cycle (TCA cycle).
  • TCA cycle citric acid cycle
  • acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacyl-CoA and P-hydroxy-P-methylglutaryl-CoA (HMG-CoA).
  • HMG-CoA Deaminated amino acids that are ketogenic, such as leucine, also feed the TCA cycle, forming acetoacetate & ACoA and thereby produce ketones.
  • the three ketone bodies, each synthesized from acetyl-CoA molecules, are:
  • Acetoacetate which, if not oxidized to form usable energy, is the source of the two other ketone bodies below.
  • Acetone which is generated through the decarboxylation of acetoacetate.
  • Decarboxylation of acetoacetate may occur spontaneously or through the enzyme acetoacetate decarboxylase.
  • the body releases acetone by breathing it off.
  • ⁇ -hydroxybutyrate which is not, in the technical sense, a ketone according to IUPAC nomenclature. It is generated through the action of the enzyme D-P-hydroxybutyrate dehydrogenase on acetoacetate.
  • the up-regulated genes related to lipid breakdown are the genes reported in table VIII)
  • the down-regulated genes related to lipid biosynthesis are the genes reported in table IX 9 and/or in inflammatory response (genes reported in Table X).
  • TFEB protein is chosen from the group consisting of a homologue, a derivative, an equivalent, and a fragment of the protein.
  • the term “equivalent” will be understood to mean a peptide having at least one of the activities of the instant polypeptide.
  • "Homologue” will be understood as a polypeptide exhibiting certain modifications compared with the natural polypeptide. These modifications can be a deletion, a truncation, an extension, a chimeric fusion, and/or a mutation. Among equivalent polypeptides, those who display more than 80% homology are preferred.
  • “Derivative” refers to any polypeptides, eventually mutated, truncated, and/or extended, which have been chemically modified or contain unusual amino acids.
  • polypeptide refers to a molecular chain of amino acids having therapeutic properties for obesity and/or metabolic disorders.
  • This polypeptide if required, can be modified in vitro and/or in vivo, for example by glycosylation, myristoylation, amidation, carboxylation or phosphorylation, and may be obtained, for example, by synthetic or recombinant techniques known in the art.
  • orthologs refers to proteins in different species than the proteins SEQ ID NO. 64 in Homo sapiens that evolved from a common ancestral gene by speciation.
  • orthologs one can cite the proteins corresponding to TFEB in Mus musculus , Rattus norvegicus , Pan troglodytes, Bos Taurus, Gallus gallus, Xenopus laevis, Tetraodon nigra viridis, and Danio rerio.
  • the term “derivatives” refers to polypeptides having a percentage of identity of at least 75% with SEQ ID NO.64 or ortholog thereof, preferably of at least 85%, as an example of at least 90%, and more preferably of at least 95%.
  • the term “derivatives” refers to polynucleotide having a percentage of identity of at least 75% with SEQ ID NO. l or ortholog thereof, preferably of at least 85%, as an example of at least 90%, and more preferably of at least 95%.
  • fragments refers to polypeptides having a length of at least 25 amino acids, preferably at least 50 amino acids, as an example at least 75 or 85 amino acids, and more preferably of at least 100 amino acids.
  • fragments refers to polynucleotides having a length of at least 25 nucleotides, preferably at least 50 nucleotides, as an example at least 75 or 85 nucleotides, and more preferably of at least 100 nucleotides.
  • percentage of identity between two amino acids sequences, means the percentage of identical amino-acids, between the two sequences to be compared, obtained with the best alignment of said sequences, this percentage being purely statistical and the differences between these two sequences being randomly spread over the amino acids sequences.
  • best alignment or “optimal alignment” means the alignment for which the determined percentage of identity (see below) is the highest. Sequences comparison between two amino acids sequences are usually realized by comparing these sequences that have been previously align according to the best alignment; this comparison is realized on segments of comparison in order to identify and compared the local regions of similarity.
  • the identity percentage between two sequences of amino acids is determined by comparing these two sequences optimally aligned, the amino acids sequences being able to comprise additions or deletions in respect to the reference sequence in order to get the optimal alignment between these two sequences.
  • the percentage of identity is calculated by determining the number of identical position between these two sequences, and dividing this number by the total number of compared positions, and by multiplying the result obtained by 100 to get the percentage of identity between these two sequences.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • the term "pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
  • the polynucleotide of the invention may also include the coding sequence of the polypeptide defined previously, additional coding sequence such as leader sequence or a proprotein sequence, and/or additional non-coding sequence, such as introns or 5 'and/or 3' UTR sequences.
  • vector refers to an expression vector, and may be for example in the form of a plasmid, a viral particle, a phage, etc.
  • Such vectors may include bacterial plasmids, phage DNA, baculovirus, yeast plasmids, vectors derived from combinations of plasmids and phage DNA, viral DNA such as vaccinia, adenovirus, fowl pox virus, and pseudorabies.
  • viral DNA such as vaccinia, adenovirus, fowl pox virus, and pseudorabies.
  • suitable vectors are known to those of skill in the art and are commercially available. The following vectors are provided by way of example.
  • Bacterial pQE70, pQE60, pQE-9 (QIAGEN), pbs, pDIO, phagescript, psiX174, pbluescript SK, pbsks, pNH8A, pNHl[beta]a, pNH18A, pNH46A (STRATAGENE), ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 (PHARMACIA).
  • the viral vector may be selected from the group of: adenoviral vectors, adeno-associated viral (AAV) vectors, pseudotyped AAV vectors, herpes viral vectors, retroviral vectors, lentiviral vectors, baculoviral vectors.
  • AAV adeno-associated viral
  • Pseudotyped AAV vectors are those which contain the genome of one AAV serotype in the capsid of a second AAV serotype; for example an AAV2/8 vector contains the AAV8 capsid and the AAV 2 genome 35 .
  • Such vectors are also known as chimeric vectors.
  • Naked plasmid DNA vectors and other vectors known in the art may be used to deliver a TFEB gene according to the present invention 36 .
  • Other examples of delivery systems include ex vivo delivery systems, which include but are not limited to DNA transfection methods such as electroporation, DNA biolistics, lipid-mediated transfection, compacted DNA-mediated transfection.
  • a viral vector can accommodate a transgene (i.e., a TFEB gene described herein) and regulatory elements.
  • a viral vector may be delivered through intravenous or intravascular injection.
  • Other routes of systemic administration include, but are not limited to, intra-arterial, intra-cardiac, intraperitoneal and subcutaneous or via local administration such as muscle injection or intramuscular administration.
  • the vector of the invention in particular the HDAd vector may be injected at a dose range between lxlOelO viral particles (vp)/kg and Ixl0el3 vp/kg.
  • a dose range between lxlOel l and Ixl0el2 vp/kg is more likely to be effective in humans because these doses are expected to result in large transduction efficiency of the liver.
  • the vector of the invention in particular the AAV vector may be injected at doses between lxlOel l vector genomes (vg)/kg and Ixl0el3 vg/kg are expected to provide high liver transduction 26 .
  • Adenoviral vector genomes do not integrate into the genome of the transduced cells and therefore vector genomes are lost in actively dividing cells 37 . Should TFEB expression fade over time, to maintain phenotypic correction it would be possible to re-administer a vector with a different serotype to overcome the neutralizing anti-Ad antibody elicited with the first administration 38 ' 39 .
  • the polynucleotide sequence preferably the DNA sequence in the vector is operatively linked to an appropriate expression control sequence(s) (promoter) to direct mR A synthesis.
  • promoter an appropriate expression control sequence(s)
  • prokaryotic or eukaryotic promoters such as CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I.
  • the expression vector also contains a ribosome binding site for translation initiation and a transcription vector.
  • the vector may also include appropriate sequences for amplifying expression.
  • the vectors preferably contain one or more selectable marker genes to provide a phenotypic trait for selection of transformed host cells such as dihydro folate reductase or neomycin resistance for eukaryotic cell culture, or such as tetracycline or ampicillin resistance in E. coli.
  • host cell or host cell genetically engineered relates to host cells which have been transduced, transformed or transfected with the polynucleotide or with the vector described previously.
  • bacterial cells such as E. coli, Streptomyces, Salmonella typhimurium, fungal cells such as yeast, insect cells such as Sf9, animal cells such as CHO or COS, plant cells, etc.
  • fungal cells such as yeast
  • insect cells such as Sf9
  • animal cells such as CHO or COS, plant cells, etc.
  • said host cell is an animal cell, and most preferably a human cell.
  • Fig. 1 TFEB regulates liver fat catabolism in response to starvation.
  • A Toluidin blue staining of liver sections isolated from fed and 24-h-fasted Tcfeb- i KO and control mice. Arrows indicate lipid droplets.
  • B Electron microscopy of hepatocytes from starved samples in (A).
  • L lipid droplets, (right panel) Representative example of lipid droplets from control and Tcfeb- Li KO hepatocyte. Bar graphs show quantification of number and size of lipid droplets/hepatocyte. Values are mean+s.d. of at least 10 cell/mice. *P ⁇ 0.05; ***P ⁇ 0.001 Scale bar 2 ⁇ .
  • TFEB decreases body weight by inducing lipid catabolism and energy expenditure.
  • A Body weight curves of 5 to 20-week-old mice.
  • B Epididymal fat pad from 2-month-old-mice.
  • C,D Total serum cholesterol and triglyceride levels in fed 2-month-old-mice.
  • TFEB prevents diet-induced obesity and metabolic syndrome.
  • B Whole body composition analysis (Echo MRI) of the same mice as in (A) after 10 weeks of HFD.
  • Fig. 4. The TFEB lipid metabolism network.
  • A The 124 genes with a known role in the lipid metabolic process, whose expression is perturbed by TFEB overexpression, are represented as coloured circles and assigned to specific lipid breakdown (left) or lipid biosynthesis (right) subcategories. The percentages of up-regulated (red circles) and down-regulated genes (green circles) are shown both for the two main groups and for each sub-category.
  • TFEB functional domains TFEB contains adjacent helix-loop-helix (HLH) and leucine zipper (LZ) domains flanked by an upstream basic region, as illustrated at http ://www.uniprot.org/uniprot/P 19484.
  • HHL helix-loop-helix
  • LZ leucine zipper
  • HDAd-TFEB Inverted terminal repeat (ITR) means sequences necessary for virus replication, ⁇ means the packaging sequence that ensures packaging of the vector DNA into virions, "stuffer” means human genomic DNA sequences or other non-transcribed DNA sequences used to increase the vector insert size.
  • WPRE means the niRNA-stabilizing post- transcriptional regulatory element from the woodchuck hepatitis virus.
  • BGHpA means the bovine growth hormone polyadenylation signal. This sequence represents a specialized termination sequence for protein expression in eukaryotic cells.
  • HDAd-TFEB contains the human TFEB transgene under the control of a liverspecific PEPCK promoter.
  • the expression cassette contains the ApoAI intron, the woodchuck hepatitis post-transcriptional regulatory element (WPRE), the Locus Control Region (LCR) from the apoE locus and the human growth hormone poly A (GHpA).
  • WPRE woodchuck hepatitis post-transcriptional regulatory element
  • LCR Locus Control Region
  • GpA human growth hormone poly A
  • ITR Adenoviral inverted terminal repeats
  • ⁇ packaging signal
  • Fig. 7 Accumulation of lipid droplets in liver of 24h-fasted Tcfeb-Li KO mice. Oil red O staining of liver sections isolated from mice fed ad libitum and 24h-fasted. Original magnification 40X.
  • TFEB is not involved in hepatic gluconeogenesis during starvation.
  • Pyruvate tolerance test in Tcfeb-Li KO and control mice. Following an 18h-fast, blood glucose concentrations were measured via tail bleed before (0) and at times indicated after pyruvate injection. Values are mean ⁇ sd. n 5.
  • TFEB prevents diet-induced obesity and metabolic syndrome.
  • Total serum insulin, leptin, triglyceride and cholesterol levels in control and HDAd-TFEB mice kept on high-fat diet (HFD) for 10 weeks. Values are mean ⁇ sd. n 10. *P ⁇ 0.05; ****P ⁇ 0.0001 compared to control.
  • Fig. 13. TFEB rescues the metabolic syndrome in Ob/Ob mice.
  • Plasma triglyceride (d) fractions were analyzed by fast performance liquid chromatography (FPLC).
  • FPLC fast performance liquid chromatography
  • TFEB overexpression increases the expression level of both autophagy/lysosomal and lipid metabolism genes.
  • Fig. 15 Regulatory overlap between starvation response and TFEB overexpression in liver. Genes involved in lipid metabolism represent 9% and 21% of the differentially-expressed genes in the overTFEB and WT starved microarray datasets, respectively. The Venn diagram shows that 52 of the lipid metabolism genes are overlapping from the two datasets. Of those, the majority (93%) of the catabolic lipid genes are upregulated, while the majority (80%>) of the anabolic lipid genes are downregulated.
  • Fig. 16. TFEB coordinates the liver starvation response. Starvation induces TFEB nuclear translocation through the inhibition of mTORCl -mediated TFEB phosphorylation.
  • TFEB activates lysosomal and autophagy genes, a process that induces lipophagy and the generation of FFA.
  • TFEB also independently controls the oxidation of FFAs in mitochondria and peroxisomes through the direct regulation of PGC 1 a and PPARa genes
  • Table V list of 124 genes (out of 1384 differential expressed genes, GSE35015) with a known role in lipid metabolic process. For each gene, the specific lipid breakdown or lipid biosynthesis sub-category and the signed ratio (Fold Change >1.5; GSE35015) have been reported. The genes up -regulated and down-regulated are highlighted in red and in green, respectively. The presence of CLEAR sites (consensus TFEB target sites) in the promoter region of the genes has been reported (Yes). The asterisk (*) indicates the genes mapped in a specific sub-category as assessed by literature (Gachon, F. et al.
  • Proline- and acidic amino acid- rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor alpha (PPARalpha) activity.
  • Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high- fat/high-carbohydrate diets.
  • Table VI list of 162 probesets corresponding to the 132 genes differentially expressed both in WT starved microarray dataset (GSE36510) and in the liver microarray dataset following TFEB overexpression (GSE35015).
  • Table VII list of 52 genes with a known role in lipid metabolism.
  • the 52 genes represent the 39% of the genes differentially expressed (refer to Supplementary Table 4) both in the liver microarray dataset following TFEB overexpression (overTFEB; GSE35015) and in the WT starved microarray dataset (GSE36510).
  • overTFEB overTFEB
  • GSE36510 WT starved microarray dataset
  • Table VIII Lipid Breakdown genes, list of 52 genes with a known role in the different lipid breakdown sub-categories.
  • Table IX Lipid Biosynthesis genes, list of 72 genes with a known role in the different lipid biosynthesis sub-categories.
  • Table X Inflammatory response genes, List of 66 genes with a known role in the inflammatory response
  • Tcfeb-fiox (Tcfeb-Li KO ) mouse line generation was described previously (5).
  • the transgenic line expressing the CRE under the Albumin promoter (ALB-CRE) was obtained from the Jackson laboratory. All mice were maintained in a C57BL/6 strain background and housed in a temperature-controlled environment with 12 hr light/dark cycles. Fasting experiments were carried for 24h starting from the morning otherwise indicated.
  • age- matched male mice had free access to water and were fed ad libitum a Western-style diet (Harlan Teklad TD 88137) containing 21% (w/w) total lipid (42% calories as anhydrous milk fat). Body weights were recorded bi-monthly.
  • mice were euthanatized prior to organ harvest.
  • the control mice were TcFEB loxP/loxP mice that did not have the Albumin Cre transgene. All experiments were approved by the Committee on Animal Care at the Baylor College of Medicine and conform to the legal mandates and federal guidelines for the care and maintenance of laboratory animals.
  • HP Ad virus production was approved by the Committee on Animal Care at the Baylor College of Medicine and conform to the legal mandates and federal guidelines for the care and maintenance of laboratory animals.
  • HDAd-TFEB containing hTFEB expression cassette was composed of the following elements (from 5' to 3'): a liver-restricted rat phosphoenolpyruvate carboxykinase promoter (16), the ApoAI intron, the hTFEB cDNA, the woodchuck hepatitis virus posttranscriptional regulatory element, the ApoE locus control region, and the human growth hormone poly(A).
  • HDAd was produced in 116 cells with the helper virus AdNG163 as described in detail elsewhere (77, 18). Characterization of the vector revealed the expected genomic structure and a level of helper virus contamination of 0.05%> as previously described (17).
  • Hepatic transduction was achieved by intravenous administration (retro-orbital) of approximately 400ml corresponding to 10 13 Viral particle/kg.
  • intravenous administration retro-orbital
  • As control for this experiment the authors used age sex matched mice infected with 10 13 viral particle/kg transgeneless HDAd vector.
  • mice were injected intraperitoneally with 20 mg/mL Avertin and then subjected to intracardial perfusion using 4% paraformaldehyde (PFA) in PBS. Liver were dissected and post-fixed with buffered 4% PFA overnight at 4°C, then washed with PBS and cryoprotected in successive sucrose solutions diluted with PBS: 5% for 30 minutes, 10% for several hours, and 20% overnight at 4°C; finally embedded in OCT. Cryostat sections were cut at 10mm. Hematoxylin/eosin and Oil red O staining protocols were performed following the IHC world protocols (http://www.ihcworld.com).
  • Ultra-thin sections of approximately 70nm were obtained using an RMC MT6000-XL ultramicrotome and a Diatome Ultra45 diamond knife, and collected on 150 hex-mesh copper grids. The ultra-thin sections were then stained with Reynold's lead citrate for 4 minutes. The air-dried samples were examined on a Hitachi H7500 transmission electron microscope and images were captured using a Gatan US 1000 digital camera and Digital Micrograph vl .82.366 software.
  • mice were injected with glucose (1.5 mg/g body weigh) after 6 h fasting.
  • ITT 4h fasted mice were injected (i.p.) with insulin (0.75 milliunit/g body weight, Humulin R; Eli Lily).
  • ITT 4h fasted mice were injected (i.p.) with insulin (0.75 milliunit/g body weight, Humulin R; Eli Lily).
  • ITT 4h fasted mice were injected (i.p.) with insulin (0.75 milliunit/g body weight, Humulin R; Eli Lily). Experiments were performed between 10 AM and 12 PM. Blood was taken before and 15, 30, 60, and 120 min after treatment for determination of glucose and insulin levels.
  • pyruvate tolerance test following an 16-h fast, mice received an i.p. injection 2 g/kg of sodium pyruvate (Sigma) dissolved in PBS. Blood glucose concentrations were measure via tail bleed before and at times indicated after injection.
  • Liver triglycerides, free fatty acids, and cholesterol were extracted as follows: Briefly, pulverized liver was homogenized in PBS, then extracted using chloroform/methanol (2: 1), dried overnight and resuspended in a solution of 60% butanol 40% Triton X-l 14/methanol (2: 1). Measurements normalized to protein content in initial homogenate by DC Protein assay (Bio-Rad).
  • mice Whole body compositions of mice were analyzed by EchoMRI (Echo Medical Systems) according to the manufacturer's instructions.
  • OCR oxygen consumption rate
  • mice were deeply anaesthetized with Avertin (240 mg/kg) and perfused first with 25 ml of HBSS (Sigma H6648) supplemented with lOmM HEPES and 0.5mM EGTA and after with a similar solution containing 100 U/ml of Collagenase (Wako) and 0.05 mg/ml of Trypsin inhibitor (Sigma). Liver was dissociated in a petri dish, cell pellet was washed in HBSS once and in 50% percoll gradient (Perkin Helmer) and plated at density of 5* 10 5 cells/35mm dish.
  • Cells were cultured in William's medium E supplemented with 10%FBS, 2mM glutamine, 0.1 mM Insulin, 1 mM Dexamethasone and pen/strep.
  • HBSS (+ CaCl 2 and MgS0 4 ; GIBCO) supplemented with 1 OmM HEPES (GIBCO) and cultured for 24h prior harvesting.
  • Venn diagrams and pie charts were generated using custom annotation scripts.
  • Microarray hybridization Total RNA (3 ⁇ g) was reverse transcribed to single-stranded cDNA with a special oligo (dT) 24 primer containing a T7 RNA promoter site, added 3' to the poly-T tract, prior to second strand synthesis (One Cycle cDNA Synthesis Kit by Affymetrix, Fremont, CA, USA). Biotinylated cRNAs were then generated, using the GeneChip IVT Labeling Kit (Affymetrix).
  • RNA extracted from the liver of three mice was extracted from the liver of three not-injected mice was used as a control.
  • total RNA was extracted from the liver of two wt mice; RNA extracted from the liver of two wt mice was used as control.
  • GOEA Gene Ontology Enrichment Analysis
  • the list of 1814 probesets was mapped on the GO hierarchy (25, 26) rooted in the Lipid Metabolic Process (GO:0006629) term.
  • the authors considered the "children" of the two main sub-categories of the Lipid Metabolic Process: the lipid catabolic process (GO: 0016042) and the lipid biosynthetic process (GO:0008610).
  • the lipid catabolic process (GO:0016042) contains 6 sub-categories, while the lipid biosynthetic process (GO:0008610) contains 15 sub-categories.
  • the cellular lipid catabolic process (GO:0044242), which is one of the "children" of the lipid catabolic process, was divided in its 7 sub-categories for the analysis.
  • the two "children" of the lipid oxidation (GO:0034440) were also analyzed.
  • the authors introduced one more sub-category, the fatty acid binding and transport, to map genes as indicated in literature.
  • the 1384 differentially expressed genes were mapped to 20 sub-categories (http://www.geneontology.org/ (25, 26)): 7 sub-categories of the lipid catabolic process, 1 1 sub-categories of the lipid biosynthetic process, 1 sub-category of the lipid oxidation and the fatty acid binding and transport.
  • the total number of the mapped genes was 124 (table V).
  • the distribution of these genes among the 20 sub-categories was visualized in Cytoscape, an open source platform for complex network analysis and visualization (27).
  • the threshold for statistical significance chosen for the comparison between the overTFEB dataset and WT starved dataset was FDR ⁇ 0.05 and absolute Fold Change >1.5 : the authors thus selected 162 probesets corresponding to 132 differentially expressed genes (table VI).
  • the GOEA on the list of 132 genes was performed as described above and reported in table IV.
  • mice overexpressing TFEB-FLAG in liver were previously described (5). As control were used transgeneless littermate.
  • the liver was isolated from 5 days old mice and incubated in 1% formaldehyde for 10 minutes at room temperature to cross-link DNA to associated proteins.
  • the tissue was washed twice with ice-cold phosphate buffered saline (PBS) containing 0.125 M glycine and protease inhibitors (PI; complete protease inhibitor cocktail tablets, Roche Applied Science, Indianapolis, IN) and then homogenized in lysis buffer (10 mM Tris-HCl pH 7.5, 10 mM NaCl, 3 mM MgC12, 0.5% NP40) containing PI.
  • PBS ice-cold phosphate buffered saline
  • PI protease inhibitor cocktail tablets
  • the lysate was centrifuged for 5 minutes at 3,000 rpm and 4°C, and the nuclear pellet was sonicated with a Branson Sonifier 450 for 6 seconds at power level 6.
  • the homogenate was then digested with 300 U of micrococcal nuclease for 5 minutes at 37°C (Worthington Biochemical Corporation, Lakewood, NJ) to generate fragments with an average length of -100-200 bps, as determined empirically by agarose gel electrophoresis of the fragmented chromatin sample.
  • chromatin For immunoprecipitation, 200 ⁇ of chromatin was diluted 1 : 10 in ChIP dilution buffer (Millipore Corporation, Billerica, MA) and 1% of the diluted sample was set aside for input. The sample was precleared with streptavidin beads (Thermo scientific) at 4°C for 3 hours. The precleared lysate was incubated overnight ⁇ g of biotinilated anti-Flag antibody (BioM2 SIGMA).
  • the beads were washed at room temperature (for 5 minutes each) with 700 ⁇ of low salt buffer, high salt buffer, LiCl buffer (Millipore Corporation, Billerica, MA), and TE buffer (10 mM Tris-HCl pH 7.4, 1 mM EDTA pH 8.0). Elution was performed twice in 250 ⁇ of fresh elution buffer (1% SDS, 0.1 M NaHC03) for 15 minutes at room temperature. The eluates were combined, 20 ⁇ of 5 M NaCl was added, and samples were incubated overnight at 65 °C to reverse the crosslinks. The input DNA was diluted in freshly made elution buffer to a volume of 500 ⁇ , and cross-link reversal was performed.
  • Acot2 F AAGAAGCCGTGAACTACCTGCG CD36 TCACTCACACACGGCAAAAT
  • Acot2 R TGTGATGCCCTTCAGGAAGGAG CD36 GCCAGATGCTTGGTCAAATC
  • Hmgcs l F GGAAATGCCAGACCTACAGGTG Fabp3 AGCCCCGGCTTCCTATTT ID
  • Hmgcs l-R TACTCGGAGAGCATGTCAGGCT Fabp3 GAGTGAGGAGGCGAGCAG
  • Hmgcs2-F TGCTATGCAGCCTACC GCAAG A Fabp3 CGGCTGGACAGCCTCTTTA
  • Hmgcs2-R GCCAGGGATTTCTGGACCATCT Fabp3 ATGTGATGCGAGGGCTATTT
  • transgenic mice that specifically lack TFEB in the liver (Tcfeb- i KO ), a primary player in the starvation response.
  • the liver from Tcfeb- i KO mice displayed a striking increase in lipid droplets after a 24h starvation, compared to wild type littermates, suggesting a defect in intracellular lipid degradation (Fig. 1A,B and Fig. 7). This was supported by a significant decrease in the degradation rate of an exogenously added fatty acid (i.e. palmitate) in Tcfeb-Li KO hepatocytes, demonstrating an impairment of free fatty acid (FFA) oxidation (Fig. 1C).
  • FFA free fatty acid
  • peripheral lipolysis generates FFAs that are subsequently oxidized in the liver. This results in the production of acetyl-CoA, the building block of ketone bodies.
  • Tcfeb- i KO mice showed decreased plasma levels of circulating ketone bodies after 24h-starvation compared to control mice (Fig. ID).
  • the possibility that this was due to an impairment in FFA uptake by the liver was excluded by the normal levels of circulating FFA during starvation and the normal uptake of exogenously administered FFA in Tcfeb- i KO mice (Fig. 8).
  • the starvation-induced depletion of fat body mass was impaired in Tcfeb- i KO mice compared to controls, whereas the depletion of lean mass was unchanged, as a secondary consequence of an impaired fat breakdown by the liver (Fig. IE).
  • No differences in gluconeogenic rate were observed between Tcfeb- i KO and control mice (Fig. 9). Together these data strongly suggest that TFEB controls the liver response to starvation by regulating the rates of FFA oxidation and ketogenesis.
  • TFEB helper-dependent adenoviral vector that expresses the human TFEB cDNA (HDAd- TFEB, Fig. 6) under the control of a liver-specific promoter and enhancer (6) and injected it retro-orbitally into 5 weeks old C57BL/6 mice.
  • Fig. 2A When fed with a regular chow diet, HDAd-7FE5-injected mice were significantly leaner than controls (Fig. 2A), with a decreased deposition of body fat (Fig. 2B).
  • Tcfeb- Li KO mice showed an increase in peripheral adiposity but no significant changes in body weight compared to controls (Fig. 2A,B).
  • HDAd-7FE5-injected mice had lower plasma levels of total cholesterol and triglycerides, associated with a reduction of VLDL, while HDL was largely unaffected (Fig. 2C-F).
  • HDAd-7FE5-injected mice also showed lower levels of circulating leptin, insulin and glucose, and higher levels of adiponectin (Fig. 2G-J). The levels of these serum parameters in Tcfeb- i KO mice showed no differences compared to controls (Fig. 2C, D, G-J).
  • HDAd-7FE5-injected mice Overall the phenotype observed in HDAd-7FE5-injected mice was similar to that observed in mice that undergo caloric restriction (7), although no differences in food intake were observed between HDAd-7FE5-injected and wild type mice (Fig. 1 1). These results suggest that TFEB overexpression mimics caloric restriction by enhancing nutrient metabolism independently of food intake. Indeed, indirect calorimetric analysis demonstrated increased energy expenditure in HDAd-7FE5-injected mice compared to controls (Fig. 2K,L). Notably, HDAd-7FE5-injected mice also showed a decrease in respiratory exchange rate (RER) (Fig. 2M), an increase in the FFA oxidation rate (Fig. 2N) and no changes in carbohydrate oxidation (Fig. 20), further supporting the presence of an enhanced fat catabolism.
  • RER respiratory exchange rate
  • Fig. 2N an increase in the FFA oxidation rate
  • Fig. 20 no changes in carbohydrate oxidation
  • Body composition analysis revealed that the weight difference between TFEB gain- and loss-of-function mice was largely due to differences in fat accumulation, which was higher in Tcfeb- i KO and lower in HDAd-7FE5-injected mice compared to controls (Fig. 3B). Striking differences were observed in liver appearance and lipid content in the different types of mice when fed with a high-fat diet. The liver from Tcfeb- i KO mice was large, pale and filled with lipid vacuoles. Control mice fed with the same diet showed a similar, albeit milder, phenotype.
  • the liver from HDAd-7FE5-injected mice had normal reddish color, markedly reduced lipid content, and normal weight, suggesting that TFEB overexpression rescued the effects of the high-fat diet (Fig. 3C-E).
  • the abnormalities of the serum metabolic profile induced by the high-fat diet in wild-type mice which were characterized by an increase of circulating leptin, insulin, triglycerides and cholesterol, were markedly attenuated in HDAd-7FE5-injected mice (Fig. 12), which also showed an improved sugar metabolism, as demonstrated by glucose and insulin tolerance tests (Fig. 3F-H).
  • TFEB also positively regulated the expression of several genes involved in lysosome organization and autophagy (Table II and Fig. 14), consistent with previous results (3, £ IP).
  • the global control exerted by TFEB on lipid metabolism is illustrated in Figure 4A and Table V, Fig. 17.
  • the TFEB lipid metabolism network includes genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (e.g. CD36 and FABPs) and the ⁇ -oxidation of FFA in mitochondria (e.g. Cptl,Crat, Acadl Acads, Hdad) and peroxisomes (Cyp4a genes).
  • Table II Complete list of BPs related to the GOEA for the genes significantly up-regulated (773 genes in total) in the liver microarray dataset following TFEB overexpression (GSE35015). The data in this table were collected by using the DAVID online tool restricting the output to BP ALL terms.
  • Table III complete list of BPs related to the GOEA for the genes significantly down-regulated (611 genes in total) in the liver microarray dataset following TFEB overexpression (GSE35015). The data in this table were collected by using the DAVID online tool restricting the output to BP ALL terms.
  • Table IV complete list of BPs related to the GOEA for the 132 genes differentially expressed both in WT starved and in overTFEB datasets (refer to Table VI).
  • PITPNMl PITPNMl, IGHG, AAAS, NNT, CD36, ABCBIA, RAB17, CAMK1,
  • LAPTM4B MRC1, OSBPL5, MSTOl, TGFBR2, DENND1A,
  • FCGR2B FYN, SLC6A8, BAX, RAB34, SLC6A6, ABCC3, SLC18A1,
  • GLRX GLRX, TES, TXNIP, CPT1B, ABCA8B, ABCA8A, FADS 2, STAB2,
  • GLRX GLRX, TES, TXNIP, CPT1B, ABCA8B, ABCA8A, FADS 2, STAB2,
  • NAGK NAGK
  • AKR1A4 GALK1
  • INSIG2 CYP7A1
  • MTPN MTPN
  • PCYT1A PCYT1A
  • CHPTl CHPTl, CPTIA, GDPDl, EBPL, RENBP, G6PC, LRAT, PKLR, GYG,
  • G6PC ST8SIA4, PKLR, GYG, LOC100047575, FABP5, XYLB
  • GOTERM_ GO:0005996 ⁇ monosaccharide AKR1A4, PDHAl, PDK1, GPD2, PDK2, WDTC1, HKDCl, PDK4,
  • GOTERM_ LDHB G6PC, GNPDAl, HKDCl, PKLR, PGAMl, BPGM, PDHAl,
  • MOGAT2 PIK3C2G, CHKB, PI4KA, PNPLA2, IG PIGP,
  • PCYTIA PCYTIA, CLN8, FABP5, PIP4K2C, PTDSS2
  • GOTERM_ DDC MAOA, CHKB, CHPTl, LRAT, P4HA2, CSAD, MTPN, GPX4,
  • TLR5 CCL5, TIMP3, DTNBP1, MIF, CCL25, ANXA8, SLC1A2,
  • TLR5 TLR5, PTTG1, APOA4, SLC1A2, INSIG2, HSF2, ATG7, GPX4,
  • DCLRE1A LRAT, AAAS, ABCB1A, JUN, HSPB1, GBP1, PPP5C,
  • PPARG PPARG, PRDX2, TLR5, CCL5, CD74, MIF, APOA4, CCL25, CNR2,
  • RTN4 ENPP1, LM02, PPARG, GNA12, RHOQ, PRDX2, KIT,
  • CD36 STABl, FYN, BAX, H2-AA, ID4, LOC100047556, IGFBP3,
  • RTN4 ENPP1, LM02, PPARG, PRDX2, FOX03, ADA, TTC3,
  • G0TERM_ RTN4 ENPP1, LM02, TGFBR2, PRDX2, TTC3, CD74, EPHB2,
  • RTN4 ENPP1, LM02, PPARG, PRDX2, FOX03, TTL, CD74,
  • GOTERM_ RTN4 AR, TGFBR2, GNA12, RHOQ, GAS2, TTC3, TTL, EPHB2,
  • ATP6V0C-PS2 F0X03, ATP6V0C, ADRB3, CD9, TPPl, SLC4A4,
  • GAL3ST1 CLN6 LDH B, RPL13, ADCY6, PPP2R5C, BBX, PGAMl, MPV17, MYLI P,
  • HADHB HADHB, EPHB2, ATP6V0C, TCF21, IDH2, AI464131, GPD2,
  • OSBPL5 DNMT3A, PTGR2, UFSP1, CYP46A1, SMAD7, KLF10,
  • TKT TKT, ACACB, LOC100044230, UAP1L1, DLAT, PRPSAP1, CRYZ,
  • COMT1 ACAD10
  • CML3 RE RE
  • H LF H LF
  • PPARA CYP2J9
  • PPARG PPARG
  • GPX4 BAG2, GPX3, CHST14, NSMCE2, GPX7, DPP7, DEDD2,
  • FMOl PLA2G12A, FM02, PITRM1, GATAD2A, ACAA1A,
  • CPT1B CPT1B, PDK4, CS, FADS2, SNAI2, LOC100044896, CPT1A,
  • GOTERM GO:0008152 ⁇ metabolic FYN, GYG, ARSA, NLN, AACS, APBB1, HPGD, LRP4, MKRN1,
  • CYP2B10 CHPT1, WEE1, GNS, H HEX, SCCPDH, RENBP, LRAT,
  • RAG1AP1 CTSA, ST8SIA3, ATP6V1B2, ELK3, CYP4A12A, SBK1,
  • ENTPD2 GAL3ST1, FGD4, BHLHE22, FOXA1, FDPS, EPHX1,
  • IDH3B IDH3B, AK2, BPGM, CRAT, WIPI1, IDH3A, 2410022L05RIK,
  • CYP2C38 UBE2E2, FABP5, PIP4K2C, CYB5R3, NAMPT, SOLH,
  • LPIN1 LPIN1, DHRS7, DNASE2B, ATP6V1A, CAPN10, CYP4A31, PKLR,
  • CAMK2D CAMK2D, TOR1B, UCK1, PTS, PPAP2A, BDH1, GLRX, PTPRB,
  • AKR1B8 ADI1, SULF2, HSDL2, AKR1B3, BAX, SUMF1, CENPV,
  • LIPG LIPG, SETD8, LOC100047556, RDH16, CYP4A14, NFIC, IGFBP3,
  • LDHB LDHB
  • RPL13 ADCY6, PPP2R5C, PGA 1, BBX, MPV17, MY LIP,
  • RARB RARB
  • PDHA1 SGPL1
  • RREB1 HKDC1
  • UGCG UGCG
  • ZFP467 ZFP467
  • GPD2 GPD2, DNMT3A, UFSP1, SMAD7, KLF10, MAOA, TGFBR2,
  • KDR KDR, EPHA7, NOTCH1, COMT1, RERE, HLF, PPARA, PPARG,
  • HDAC11 CHPT1, WEE1, HHEX, RENBP, LRAT, GTF2IRD1,
  • ACOT4 ACOT3, ALASl, TPPl, SOX17, PAKl, NDUFSl, PTDSS2,
  • FAM176A DDC, SSBP3, SGK3, ACADS, CYCS, RBI, PIGQ,
  • ACADL ACADL
  • CDK4 PIGP
  • DNASE2B ATP6V1A
  • CYP4A31 CYP4A31
  • PKLR PKLR
  • PRKCZ PRKCZ, TRIB3, UPP2, DCI, ALDH3A2, AKR1A4, MTHFS, OXCT1,
  • DCLRE1A DCLRE1A, PIAS3, JUN, BACE1, CAMK1, LOC100047005,
  • PRODH PRODH, HSD17B11, ENPP5, ERMP1, ENPP2, FARS2, CH KB,
  • MME ATP6V0C-PS2, ASB13, OBFC2A, NAGK, ADA, CD74,
  • GPD2 GPD2, DNMT3A, OSBPL5, UFSP1, CYP46A1, SMAD7, KLF10,
  • CDT1 CDT1, CCNE2, USP18, P4HA2, HSF2, S PDL3A, GPX4, BAG 2,
  • PIK3C2G PI4KA
  • MMP15 PIK3C2G
  • ST6GALNAC2 PI4KA
  • MMP12 PIK3C2G
  • G6PC PIK3C2G
  • PABPN 1 ENC1, TOPBP1, PNPLA2, HDAC11, CHPT1, WEE1,
  • GNS HHEX
  • RENBP RENBP
  • LRAT LRAT
  • GTF2IRD1 PPP5C
  • ENTPD2 GAL3ST1, FGD4, BHLHE22, FOXA1, FDPS, AK2,
  • ACOT4 ACOT3, CASP6, TPPl, SRD5A3, SOX17, PAKl, NDUFSl,
  • CDK4 PIGP, LPIN1, DNASE2B, ATP6V1A, CAPN10, CYP4A31,
  • PKLR HIPK2, CD81, DDB2, UCHL5, UBD, LOC100047575,
  • AKR1A4 TORiB, CA K2D, PPAP2A, TXNIP, PTPRB, WDTC1,
  • SETD8 LOC100047556, NFIC, RDH 16, IGFBP3, RETSAT
  • PPARGC1A PPARGC1B
  • WEE1 GNS
  • HH EX IGHG
  • DCLRE1A DCLRE1A
  • CD36 CD36, PIAS3, GTF2IRD1, JUN, BACE1, CAMK1, PPP5C,
  • MMP12 ST6GALNAC2, DNASE2B, G6PC, CAPN10, CYP4A31,
  • CD81 CD81, HIPK2, DDB2, UCHL5, UBD, CTSB, CLN8, PMPCB, CLN6,
  • PPARGC1B PPARGC1B, WEE1, HHEX, DCLRE1A, CD36, PIAS3, GTF2IRD1,
  • RAG1AP1 FARS2, ST8SIA3, ASB13, ELK3, OBFC2A, CD74,
  • EPHB2 TCF21, SBK1, RAD51L1, TEK, FGD4, DNMT3A,
  • PPARG E2F8, HLCS, PRDX2, ZEB2, CDT1, CCNE2, USP18,
  • GYG GYG
  • SETD8 LOC100047556, NFIC, IGFBP3, APBB1, LRP4
  • growth factor beta receptor 7 0,01443266 BMP2, FUT8, SMAD7, HIPK2, TGFBR2, ENG, HPGD 22,63686728 BP_ALL
  • aromatic compound 9 0,10512693 MTHFS, DDC, MTPN, MAOA, EPHXl, PTS, COMTl, ADA, APRT 85,92767036 BP ALL
  • GOTERM_ GO:0022402 ⁇ cell cycle CAMK2D CABLES1, SYCE2, GAS2, TOPBPl, TPD52L1, GAS1,
  • SETD8 ID4, MAPRE2, STM 1, APBB1
  • GOTERM_ TXNIP GMNN, SYCE2, TPD52L1, GAS2, TOPBPl, RBI, GAS1,
  • CCNB2 CCNB2, PLK2, CENPV, MAPRE2, SETD8, ID4, PARD6G, STMN1,

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Abstract

The present invention refers to a vector for gene therapy comprising a TFEB coding sequence under the control of a promoter able to efficiently express said TFEB coding sequence, to host cell comprising said vector and to their use in the treatment of obesity and/or metabolic syndrome. The present invention also refers to a pharmaceutical composition comprising the vector or the host cell of the invention for therapy and to a method of treatment of obesity and/or metabolic syndrome.

Description

USE OF TFEB FOR TREATING OBESITY
TECHNICAL FIELD
The present invention relates to a vector comprising a TFEB coding sequence under the control of a promoter able to efficiently express said TFEB coding sequence for use in the treatment of obesity and/or metabolic syndrome, to a host cell comprising said vector, pharmaceutical compositions and uses thereof.
BACKGROUND ART
The liver plays a major role in the adaptation to starvation (7, 2). The transcription factor EB (TFEB), a master regulator of lysosomal biogenesis and autophagy (3, 4), is activated by starvation and participates in a lysosomal nutrient-sensing mechanism (5).
The authors recently identified transcription factor EB (TFEB), a member of the basic helix- loop-helix leucine-zipper family of transcription factors, as a master regulator of lysosomal function and autophagy (3-4). The DNA-binding factor TFEB contains adjacent helix-loop-helix (HLH) and leucine zipper (LZ) domains flanked by an upstream basic region (Fig. 5). Efficient DNA-binding requires dimerization with itself or with another MiT/TFE family member such as TFE3 or MITF. Previous data indicated that TFEB activity is regulated by starvation (4).
The document WO 2010/0921 12 relates to TFEB protein, synthetic or biotechnological functional derivative thereof, peptide fragments thereof, chimeric molecules comprising the TFEB protein, synthetic or biotechnological functional derivative thereof acting either directly or indirectly on a CLEAR element. However, the document is silent concerning obesity or metabolic syndrome. SUMMARY OF THE INVENTION
To study the physiological role of TFEB the authors generated transgenic mice that specifically lack TFEB in the liver (Tcfeb- iKO), a primary player in the starvation response.
In the present invention the authors show that TFEB regulates key genes involved in lipid breakdown, which in the absence of TFEB failed to respond to starvation. TFEB loss of function in the mouse liver resulted in an impaired lipid catabolism and ketogenesis. Conversely, TFEB delivery to the liver increased energy expenditure and lipid breakdown and rescued the metabolic syndrome in both diet- and genetically-induced obese mice. This regulatory mechanism, which may have evolved to coordinate the adaptation to food deprivation, is a promising therapeutic target for disorders of lipid metabolism. It is therefore an object of the invention a vector comprising a TFEB coding sequence, or a functional or allelic variant or derivative or fragment thereof, under the control of a promoter able to efficiently express said TFEB coding sequence for use in the treatment of obesity and/or metabolic syndrome. Preferably the treatment is by gene therapy.
The above TFEB functional variant can be a TFEB mutant, e.g. TFEB(S142A) and TFEB(S211 A) mutant.
Preferably the TFEB coding sequence (NCBI GenelD = 7942; nt = NM 007162, protein = NP 009093) is comprised in the sequence being essentially SEQ ID No. 1.
The vector according the invention is preferably a viral vector, more preferably selected from the group consisting of: adenoviral vectors, lentiviral vectors, retroviral vectors, adeno associated vectors (AAV) or naked plasmid DNA vectors, even more preferably belonging to the group of: helper-dependent adenoviral vectors.
The vector according the invention preferably comprises a liver specific promoter and/or regulatory sequences. Said liver specific promoter is preferably a phosphoenolpyruvate carboxykinase (PEPCK) promoter having essentially the sequence of SEQ ID No. 2.
Said liver regulative sequence is preferably the liver specific enhancer Locus Control Region (LCR) from the apoE locus having essentially the sequence of SEQ ID No. 3.
In a preferred embodiment of the invention the above vector comprises a construct having essentially the sequence of SEQ ID No.4. Preferably the vector of the invention enhances lipid breakdown.
It is a further object of the invention an host cell transformed by the vector of the invention for use in the treatment of obesity and/or metabolic syndrome.
It is a further object of the invention a viral particle containing the vector of the invention for use in the treatment of obesity and/or metabolic syndrome.
It is a further object of the invention a pharmaceutical composition comprising the vector of the invention or the host cell of the invention or the viral particle of the invention for use in the treatment of obesity and/or metabolic syndrome.
Another object of the invention is a method of treatment of obesity and/or metabolic syndrome of a subject in need thereof, said method comprising administering an effective amount of the pharmaceutical composition as above described.
A further object of the invention is TFEB coding sequence, protein or a functional or allelic variant thereof for use in the treatment of an obesity and/or metabolic syndrome.
Another object of the invention is a method of treatment of obesity and/or metabolic syndrome comprising administering a therapeutically effective amount of TFEB coding sequence, protein or a functional or allelic variant thereof or of a suitable amount of a pharmaceutical composition comprising TFEB coding sequence, protein or a functional or allelic variant thereof to a patient in need thereof.
A further object is a method for enhancing lipid breakdown comprising the administration of TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof.
In preferred embodiments the administration of TFEB is made by gene therapy or by the administration of a pharmaceutical composition comprising TFEB coding sequence, protein or a functional or allelic variant thereof.
In the above method TFEB is overexpressed.
In the above method, the TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof preferably enhances free fatty acid (FFA) catabolism and ketogenesis and/or regulates genes expression by up-regulating genes related to lipid breakdown and/or down-regulating genes related to lipid biosynthesis and/or in inflammatory response. In the above method, TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof preferably acts through the binding to said genes promoters and/or the up-regulated gene is PGCla and/or PPARa.
Preferably the PGCla coding sequence (NCBI Gene ID: 10891; nt = NM O 13261, protein = NP 037393) is comprised in the sequence being essentially SEQ ID No. 5.
Preferably the PPARa coding sequence (NCBI Gene ID: 5465; nt = NM 005036, protein = NP 005027) is comprised in the sequence being essentially SEQ ID No. 6.
In the present invention preferably the therapy is a gene therapy.
In the present invention a synthetic or biotechnological functional derivative of a protein, peptide fragments of a protein, chimeric molecules comprising the TFEB protein, synthetic or biotechnological functional derivative thereof are defined as molecules able to maintain the therapeutic effect of TFEB, i.e the treatment of obesity and/or metabolic syndrome. A functional derivative of TFEB may be a sequence comprising the sequence of TFEB and the sequence of an extra non endogenous nuclear localization signal.
The present invention provides pharmaceutical compositions comprising: a) an effective amount of a vector as described herein or an effective amount of a transformed host cell as described herein, and b) a pharmaceutically acceptable carrier, which may be inert or physiologically active.
As used herein, "pharmaceutically-acceptable carriers" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, and the like that are physiologically compatible. Examples of suitable carriers, diluents and/or excipients include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combination thereof. In many cases, it will be preferable to include isotonic agents, such as sugars, polyalcohols, or sodium chloride in the composition. In particular, relevant examples of suitable carrier include: (1) Dulbecco's phosphate buffered saline, pH ~ 7.4, containing or not containing about 1 mg/ml to 25 mg/ml human serum albumin, (2) 0.9% saline (0.9% w/v sodium chloride (NaCl)), and (3) 5% (w/v) dextrose; and may also contain an antioxidant such as tryptamine and a stabilizing agent such as Tween 20.
The pharmaceutical compositions encompassed by the present invention may also contain a further therapeutic agent for the treatment of obesity and/or metabolic syndrome.
The compositions of the invention may be in a variety of forms. These include for example liquid, semi-solid, but the preferred form depends on the intended mode of administration and therapeutic application. Typical preferred compositions are in the form of injectable or infusible solutions. The preferred mode of administration is parenteral (e.g. intravenous, intramuscular, intraperinoneal, subcutaneous). In a preferred embodiment, the compositions of the invention are administered intravenously as a bolus or by continuous infusion over a period of time. In another preferred embodiment, they are injected by intramuscular, subcutaneous, intraarticular, intrasynovial, intratumoral, peritumoral, intralesional, or perilesional routes, to exert local as well as systemic therapeutic effects.
Sterile compositions for parenteral administration can be prepared by incorporating the vector or host cell as described in the present invention in the required amount in the appropriate solvent, followed by sterilization by micro filtration. As solvent or vehicle, there may be used water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combination thereof. In many cases, it will be preferable to include isotonic agents, such as sugars, polyalcohols, or sodium chloride in the composition. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Sterile compositions for parenteral administration may also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other injectable sterile medium.
There may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.
The doses depend on the desired effect, the duration of the treatment and the route of administration used and may be determined easily by the skilled person in the art using known methods. As well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently.
In the present invention a metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. Some studies have shown the prevalence in the USA to be an estimated 25% of the population, and prevalence increases with age. Metabolic syndrome is also known as metabolic syndrome X, cardiometabolic syndrome, syndrome X, insulin resistance syndrome, Reaven's syndrome (named for Gerald Reaven), and CHAOS (in Australia).
Most patients are older, obese, sedentary, and have a degree of insulin resistance. Stress can also be a contributing factor. The most important factors are weight, genetics, endocrine disorders, aging, and sedentary lifestyle, (i.e., low physical activity and excess caloric intake).
There is debate regarding whether obesity or insulin resistance is the cause of the metabolic syndrome or if they are consequences of a more far-reaching metabolic derangement. A number of markers of systemic inflammation, including C-reactive protein, are often increased, as are fibrinogen, interleukin 6, tumor necrosis factor-alpha (TNFa), and others. Some have pointed to a variety of causes, including increased uric acid levels caused by dietary fructose.
Currently, different sets of defining criteria for metabolic syndrome are set out by different sources:
The International Diabetes Federation consensus worldwide definition of the metabolic syndrome (2006) is: Central obesity (defined as waist circumference with ethnicity- specific values) and any two of the following:
• Raised triglycerides: > 150 mg/dL (1.7 mmol/L), or specific treatment for this lipid abnormality;
• Reduced high-density lipoprotein (HDL) cholesterol: < 40 mg/dL (1.03 mmol/L) in males, < 50 mg/dL (1.29 mmol/L) in females, or specific treatment for this lipid abnormality;
• Raised blood pressure (BP): systolic BP > 130 or diastolic BP >85 mm Hg, or treatment of previously diagnosed hypertension;
· Raised fasting plasma glucose (FPG): >100 mg/dL (5.6 mmol/L), or previously diagnosed type 2 diabetes.
The World Health Organization 1999 criteria require the presence of any one of diabetes mellitus, impaired glucose tolerance, impaired fasting glucose or insulin resistance, and two of the following:
· Blood pressure: > 140/90 mmHg; • Dyslipidemia: triglycerides (TG): > 1.695 mmol/L and HDL cholesterol (HDL-C) < 0.9 mmol/L (male), < 1.0 mmol/L (female);
• Central obesity: wais hip ratio > 0.90 (male); > 0.85 (female), or body mass index > 30 kg/m2;
• Microalbuminuria: urinary albumin excretion ratio > 20 μg/min or albumin: creatinine ratio > 30 mg/g.
The US National Cholesterol Education Program Adult Treatment Panel III (2001) requires at least three of the following:
• Central obesity: waist circumference > 102 cm or 40 inches (male), > 88 cm or 36 inches(female);
• Dyslipidemia: TG > 1.7 mmol/L (150 mg/dl);
• Dyslipidemia: HDL-C < 40 mg/dL (male), < 50 mg/dL (female);
• Blood pressure > 130/85 mmHg (or treated for hypertension);
• Fasting plasma glucose > 6.1 mmol/L (110 mg/dl).
In the present invention by enhancing lipid breakdown it is meant that at least one of the following pathway related to lipid breakdown is positively regulated by the molecules of the present invention: glycerolipid catabolism, fatty acid binding and transport, lipid and fatty acid catabolism, membrane lipid catabolism, fatty acid oxidation, isoprenoid catabolism, steroid catabolism, sphingolipid catabolism, negative regulation of lipid biosynthetic process.
In the present invention enhancing free fatty acid (FFA) catabolism and ketogenesis is defined considering that free fatty acids (FFA) are non-esterified fatty acid, released by the hydrolysis of triglycerides within adipose tissue. Free fatty acids can be used as an immediate source of energy by many organs and can be converted by the liver into ketone bodies.
Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, in the end generating acetyl-CoA, the entry molecule for the citric acid cycle, the main energy supply of animals. It includes three major steps:
Lipolysis of and release from adipose tissue
Activation and transport into mitochondria
β -oxidation
The breakdown of fatty acids is known as lipolysis. The products of lipolysis, free fatty acids, are released into the bloodstream and circulate throughout the body.
Fatty acids must be activated before they can be carried into the mitochondria, where fatty acid oxidation occurs. This process occurs in two steps catalyzed by the enzyme fatty acyl-CoA synthetase. The inner mitochondrial membrane is impermeable to fatty acids and a specialized carnitine carrier system operates to transport activated fatty acids from cytosol to mitochondria.
Once inside the mitochondria, the β-oxidation of fatty acids occurs. The final product is acetyl- CoA, the entry molecule for the citric acid cycle.
Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown. Ketone bodies are produced mainly in the mitochondria of liver cells, and synthesis physiologically occurs in response to unavailability of blood glucose. This is caused by low glucose levels in the blood, after exhaustion of cellular carbohydrate stores, such as glycogen or, synthesis of ketones can occur due to excessively high levels of blood glucose that are unable to be stored as glycogen in liver and muscle. The production of ketone bodies is then initiated to make available energy that is stored as fatty acids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA. Under normal conditions, acetyl-CoA is further oxidized and its energy transferred as electrons to NADH, FADH2, and ATP in the citric acid cycle (TCA cycle). However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle or if activity in the TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacyl-CoA and P-hydroxy-P-methylglutaryl-CoA (HMG-CoA). Deaminated amino acids that are ketogenic, such as leucine, also feed the TCA cycle, forming acetoacetate & ACoA and thereby produce ketones.
The three ketone bodies, each synthesized from acetyl-CoA molecules, are:
Acetoacetate, which, if not oxidized to form usable energy, is the source of the two other ketone bodies below.
Acetone, which is generated through the decarboxylation of acetoacetate. Decarboxylation of acetoacetate may occur spontaneously or through the enzyme acetoacetate decarboxylase. The body releases acetone by breathing it off.
β-hydroxybutyrate, which is not, in the technical sense, a ketone according to IUPAC nomenclature. It is generated through the action of the enzyme D-P-hydroxybutyrate dehydrogenase on acetoacetate.
In the present invention the up-regulated genes related to lipid breakdown are the genes reported in table VIII), the down-regulated genes related to lipid biosynthesis are the genes reported in table IX 9 and/or in inflammatory response (genes reported in Table X).
The man skilled in the art is well aware of the standard methods for incorporation of a polynucleotide or vector into a host cell, for example transfection, lipofection, electroporation, microinjection, viral infection, thermal shock, transformation after chemical permeabilisation of the membrane or cell fusion. In the present invention TFEB protein is chosen from the group consisting of a homologue, a derivative, an equivalent, and a fragment of the protein.
As used herein, the term "equivalent" will be understood to mean a peptide having at least one of the activities of the instant polypeptide. "Homologue" will be understood as a polypeptide exhibiting certain modifications compared with the natural polypeptide. These modifications can be a deletion, a truncation, an extension, a chimeric fusion, and/or a mutation. Among equivalent polypeptides, those who display more than 80% homology are preferred. "Derivative" refers to any polypeptides, eventually mutated, truncated, and/or extended, which have been chemically modified or contain unusual amino acids.
As used herein, the term "polypeptide" refers to a molecular chain of amino acids having therapeutic properties for obesity and/or metabolic disorders. This polypeptide, if required, can be modified in vitro and/or in vivo, for example by glycosylation, myristoylation, amidation, carboxylation or phosphorylation, and may be obtained, for example, by synthetic or recombinant techniques known in the art.
As used herein, the term "orthologs" refers to proteins in different species than the proteins SEQ ID NO. 64 in Homo sapiens that evolved from a common ancestral gene by speciation. As an example of such orthologs, one can cite the proteins corresponding to TFEB in Mus musculus , Rattus norvegicus , Pan troglodytes, Bos Taurus, Gallus gallus, Xenopus laevis, Tetraodon nigra viridis, and Danio rerio.
As used herein, the term "derivatives" refers to polypeptides having a percentage of identity of at least 75% with SEQ ID NO.64 or ortholog thereof, preferably of at least 85%, as an example of at least 90%, and more preferably of at least 95%. As used herein, the term "derivatives" refers to polynucleotide having a percentage of identity of at least 75% with SEQ ID NO. l or ortholog thereof, preferably of at least 85%, as an example of at least 90%, and more preferably of at least 95%.
As used herein "fragments" refers to polypeptides having a length of at least 25 amino acids, preferably at least 50 amino acids, as an example at least 75 or 85 amino acids, and more preferably of at least 100 amino acids.
As used herein "fragments" refers to polynucleotides having a length of at least 25 nucleotides, preferably at least 50 nucleotides, as an example at least 75 or 85 nucleotides, and more preferably of at least 100 nucleotides.
As used herein, "percentage of identity" between two amino acids sequences, means the percentage of identical amino-acids, between the two sequences to be compared, obtained with the best alignment of said sequences, this percentage being purely statistical and the differences between these two sequences being randomly spread over the amino acids sequences. As used herein, "best alignment" or "optimal alignment", means the alignment for which the determined percentage of identity (see below) is the highest. Sequences comparison between two amino acids sequences are usually realized by comparing these sequences that have been previously align according to the best alignment; this comparison is realized on segments of comparison in order to identify and compared the local regions of similarity. The best sequences alignment to perform comparison can be realized, beside by a manual way, by using the global homology algorithm developed by SMITH and WATERMAN (Ad. App. Math., vol.2, p:482, 1981), by using the local homology algorithm developed by NEDDLEMAN and WUNSCH (J. MoT Biol, vol.48, p:443, 1970), by using the method of similarities developed by PEARSON and LIPMAN (Proc. Natl. Acd. Sci. USA, vol.85, p:2444, 1988), by using computer softwares using such algorithms (GAP, BESTFIT, BLAST P, BLAST N, FASTA, TFASTA in the Wisconsin Genetics software Package, Genetics Computer Group, 575 Science Dr., Madison, WI USA), by using the MUSCLE multiple alignment algorithms (Edgar, Robert C, Nucleic Acids Research, vol. 32, p: 1792, 2004 ). To get the best local alignment, one can preferably used BLAST software, with the BLOSUM 62 matrix, or the PAM 30 matrix. The identity percentage between two sequences of amino acids is determined by comparing these two sequences optimally aligned, the amino acids sequences being able to comprise additions or deletions in respect to the reference sequence in order to get the optimal alignment between these two sequences. The percentage of identity is calculated by determining the number of identical position between these two sequences, and dividing this number by the total number of compared positions, and by multiplying the result obtained by 100 to get the percentage of identity between these two sequences. The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. The polynucleotide of the invention may also include the coding sequence of the polypeptide defined previously, additional coding sequence such as leader sequence or a proprotein sequence, and/or additional non-coding sequence, such as introns or 5 'and/or 3' UTR sequences. As used herein, the term "vector" refers to an expression vector, and may be for example in the form of a plasmid, a viral particle, a phage, etc. Such vectors may include bacterial plasmids, phage DNA, baculovirus, yeast plasmids, vectors derived from combinations of plasmids and phage DNA, viral DNA such as vaccinia, adenovirus, fowl pox virus, and pseudorabies. Large numbers of suitable vectors are known to those of skill in the art and are commercially available. The following vectors are provided by way of example. Bacterial: pQE70, pQE60, pQE-9 (QIAGEN), pbs, pDIO, phagescript, psiX174, pbluescript SK, pbsks, pNH8A, pNHl[beta]a, pNH18A, pNH46A (STRATAGENE), ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 (PHARMACIA). Eukaryotic: pWLNEO, pSV2CAT, pOG44, pXTl, pSG (STRATAGENE), pSVK3, pBPV, pMSG, pSVL (PHARMACIA). However, any other vector may be used as long as it is replicable and viable in the host. In the present invention, the viral vector may be selected from the group of: adenoviral vectors, adeno-associated viral (AAV) vectors, pseudotyped AAV vectors, herpes viral vectors, retroviral vectors, lentiviral vectors, baculoviral vectors. Pseudotyped AAV vectors are those which contain the genome of one AAV serotype in the capsid of a second AAV serotype; for example an AAV2/8 vector contains the AAV8 capsid and the AAV 2 genome35. Such vectors are also known as chimeric vectors. Naked plasmid DNA vectors and other vectors known in the art may be used to deliver a TFEB gene according to the present invention36. Other examples of delivery systems include ex vivo delivery systems, which include but are not limited to DNA transfection methods such as electroporation, DNA biolistics, lipid-mediated transfection, compacted DNA-mediated transfection. Typically, a viral vector can accommodate a transgene (i.e., a TFEB gene described herein) and regulatory elements.
Various methods may be used to deliver viral vectors encoding a TFEB gene described herein into a subject in need of treatment. For example, a viral vector may be delivered through intravenous or intravascular injection. Other routes of systemic administration include, but are not limited to, intra-arterial, intra-cardiac, intraperitoneal and subcutaneous or via local administration such as muscle injection or intramuscular administration.
The vector of the invention, in particular the HDAd vector may be injected at a dose range between lxlOelO viral particles (vp)/kg and Ixl0el3 vp/kg.
A dose range between lxlOel l and Ixl0el2 vp/kg is more likely to be effective in humans because these doses are expected to result in large transduction efficiency of the liver. The vector of the invention, in particular the AAV vector may be injected at doses between lxlOel l vector genomes (vg)/kg and Ixl0el3 vg/kg are expected to provide high liver transduction26.
Adenoviral vector genomes do not integrate into the genome of the transduced cells and therefore vector genomes are lost in actively dividing cells37. Should TFEB expression fade over time, to maintain phenotypic correction it would be possible to re-administer a vector with a different serotype to overcome the neutralizing anti-Ad antibody elicited with the first administration38 '39.
The polynucleotide sequence, preferably the DNA sequence in the vector is operatively linked to an appropriate expression control sequence(s) (promoter) to direct mR A synthesis. As representative examples of such promoters, one can mentioned prokaryotic or eukaryotic promoters such as CMV immediate early, HSV thymidine kinase, early and late SV40, LTRs from retrovirus, and mouse metallothionein-I. The expression vector also contains a ribosome binding site for translation initiation and a transcription vector. The vector may also include appropriate sequences for amplifying expression. In addition, the vectors preferably contain one or more selectable marker genes to provide a phenotypic trait for selection of transformed host cells such as dihydro folate reductase or neomycin resistance for eukaryotic cell culture, or such as tetracycline or ampicillin resistance in E. coli.
As used herein, the term "host cell or host cell genetically engineered" relates to host cells which have been transduced, transformed or transfected with the polynucleotide or with the vector described previously.
As representative examples of appropriate host cells, one can cites bacterial cells, such as E. coli, Streptomyces, Salmonella typhimurium, fungal cells such as yeast, insect cells such as Sf9, animal cells such as CHO or COS, plant cells, etc. The selection of an appropriate host is deemed to be within the scope of those skilled in the art from the teachings herein. Preferably, said host cell is an animal cell, and most preferably a human cell. The present invention will be illustrated by means of non-limiting figures in reference to the following figures.
Fig. 1. TFEB regulates liver fat catabolism in response to starvation. A, Toluidin blue staining of liver sections isolated from fed and 24-h-fasted Tcfeb- iKO and control mice. Arrows indicate lipid droplets. B, Electron microscopy of hepatocytes from starved samples in (A). L=lipid droplets, (right panel) Representative example of lipid droplets from control and Tcfeb- LiKO hepatocyte. Bar graphs show quantification of number and size of lipid droplets/hepatocyte. Values are mean+s.d. of at least 10 cell/mice. *P<0.05; ***P<0.001 Scale bar 2μιη. C, Oxygen consumption rate was measured with an XF24 analyzer (Seahorse) prior and after addition of palmitic acid (0.2 mM) conjugated with BSA in primary hepatocytes isolated from control and Tcfeb- iKO mice. The vertical blue line indicates the time at which palmitate was added to cells. Values are mean+s.d. for 3 independent experiments *P<0.05 D, Total serum ketones in fed and fasted Tcfeb- iKO and control mice. E, Measurements of fat and lean mass in fed and in 24-h and 48-h fasted mice expressed as relative % to fed (0 in the graph). Indicated values are mean±s.d. for n=10 (e); n=5 (f,g) *P<0.05; **P<0.01 compared to fasted control mice.
Fig. 2. TFEB decreases body weight by inducing lipid catabolism and energy expenditure.
A, Body weight curves of 5 to 20-week-old mice. B, Epididymal fat pad from 2-month-old-mice. C,D, Total serum cholesterol and triglyceride levels in fed 2-month-old-mice. E, F, VLDL and
HDL fractions. G-J, Total serum leptin, insulin, glucose, adiponectin, in 2-month-old-mice. K,
L, Total Volume of Oxygen consumption (V02) and Carbon Dioxide (VC02) release over
72h/mouse (values are normalized with lean mass). M, Respiratory exchange ratio (RER;
VC02/V02). N, O, Fatty acid (N) and carbohydrate (O) utilization calculated from data in (M) and (N). Values are mean ± SEM (n = 10 in A and C,D,G-J; n=5 in B,E,F,K-0) *P<0.05;
**P<0.01; ***P<0.001 compared to controls, (control mice = blue; Tcfeb- iKO = green; HDAd-
7FE5-injected = red).
Fig. 3. TFEB prevents diet-induced obesity and metabolic syndrome. A, Body weight curves of male mice fed with HFD (40% calories from fat) for 10 weeks starting from 5 weeks of age (0 on the x axes). HDAd-TFEB mice were injected either 1 week before (early inj.), or 4 weeks after, (late inj.) starting the HFD, as indicated by the arrows. Values are represented as percentages of weight increase. n=10/group. *P<0.05; **P<0.01; ***P<0.001 compared to control HFD group. B, Whole body composition analysis (Echo MRI) of the same mice as in (A) after 10 weeks of HFD. C, Gross liver morphology (upper panel), H/E (middle panel), and oil red O staining of liver sections. Mice were kept in high fat diet for 12 weeks where indicated (HFD). D, Bar graph shows normalized liver weights (mean+s.d. for n=10). *P<0.05 compared to control HFD. E, Bar graph shows normalized liver lipid content (mean+s.d. for n=10). *P<0.05; **P<0.01; ***P<0.001 compared to control. F-H, Glucose and insulin tolerance tests in control and HDAd-TFEB mice challenged with HFD for 10 weeks. (F) Glucose and (G) serum insulin levels at the indicated time points after glucose challenge. (H) Glucose levels at the indicated time points after insulin challenge. n=7 group; *P<0.05; **P<0.01; ***P<0.001 compared to control, (control mice = blue, Tcfeb-L^° = green, HDAd-7FE5-injected = red). Fig. 4. The TFEB lipid metabolism network. A, The 124 genes with a known role in the lipid metabolic process, whose expression is perturbed by TFEB overexpression, are represented as coloured circles and assigned to specific lipid breakdown (left) or lipid biosynthesis (right) subcategories. The percentages of up-regulated (red circles) and down-regulated genes (green circles) are shown both for the two main groups and for each sub-category. Note that in calculating these percentages genes assigned to the "negative" regulation of lipid catabolic process and to the "negative" regulation of lipid biosynthetic process (*) have been included in the lipid breakdown and in the lipid biosynthesis groups, respectively. B, Gene expression analysis by qPCR of genes involved in lipid metabolism in the liver from either fasted or fed Tcfeb- iKO and control mice. C, gene expression analysis by qPCR of genes involved in lipid metabolism from either fasted or fed primary hepatocytes isolated from HDAd-TFEB, Tcfeb- LiKO and control mice. GAPDH and Cyclophilin were used as control genes. Bar graph shows mean ±s.d. for n=4. *P<0.05; **P<0.01; ***P<0.001 compared to the correspondent control (fed or fasted). D, Chromatin immunoprecipitation (ChIP) analysis from liver of mice fed ad libitum or 24-h fasted. Distribution of the CLEAR element in the promoter region of PGCla and PPARa Numbers indicate the distance of the binding element from the 5'UTR. The histogram shows the amount of immunoprecipitated DNA as detected by qPCR assay. Values were normalized to the input and plotted as relative enrichment over a mock control. Bar graph represent mean value ± sem *P<0.05; **P<0.01.
Fig. 5. TFEB functional domains. TFEB contains adjacent helix-loop-helix (HLH) and leucine zipper (LZ) domains flanked by an upstream basic region, as illustrated at http ://www.uniprot.org/uniprot/P 19484.
Fig. 6. HDAd-TFEB. Inverted terminal repeat (ITR) means sequences necessary for virus replication, ψ means the packaging sequence that ensures packaging of the vector DNA into virions, "stuffer" means human genomic DNA sequences or other non-transcribed DNA sequences used to increase the vector insert size. "WPRE" means the niRNA-stabilizing post- transcriptional regulatory element from the woodchuck hepatitis virus. "BGHpA" means the bovine growth hormone polyadenylation signal. This sequence represents a specialized termination sequence for protein expression in eukaryotic cells. HDAd-TFEB contains the human TFEB transgene under the control of a liverspecific PEPCK promoter. The expression cassette contains the ApoAI intron, the woodchuck hepatitis post-transcriptional regulatory element (WPRE), the Locus Control Region (LCR) from the apoE locus and the human growth hormone poly A (GHpA). Adenoviral inverted terminal repeats (ITR) and packaging signal (Ψ) are shown. Not drawn to scale.
Fig. 7. Accumulation of lipid droplets in liver of 24h-fasted Tcfeb-LiKO mice. Oil red O staining of liver sections isolated from mice fed ad libitum and 24h-fasted. Original magnification 40X. Fig. 8. TFEB does not regulate plasma fatty acid uptake by the liver, a, level of serum free fatty acid (FFA) in 24h-fasted mice. n=10 (values are mean ± sd). b, triglyceride clearance in 24h-fasted Tcfeb-LiKO mice and control. Triglycerides were measured at the indicated time point after oral administration of FFA (Intralipid). Values are mean ± sd. n=5.
Fig. 9. TFEB is not involved in hepatic gluconeogenesis during starvation. Pyruvate tolerance test in Tcfeb-LiKO and control mice. Following an 18h-fast, blood glucose concentrations were measured via tail bleed before (0) and at times indicated after pyruvate injection. Values are mean ± sd. n=5.
Fig. 10. Level of hTFEB expression 4 months after HDAd-TFEB viral delivery. mRNA level of TFEB in liver samples isolated from control and HDAd-TFEB injected mice. Primers were designed to recognize both human and mouse gene. Values are mean ± sd. n=3.
Fig. 11. Food intake in control, Tcfeb-LiKO and HDAd-TFEB mice. Food intake was measured over a period of 72h. Tcfeb-LiKO mice do not eat more compared to controls in both chow and high-fat diets. HDAd-TFEB infected mice have an increased food intake compared to controls only when fed with a high- fat diet. Values are mean ± sd. n=5. *P<0.05
Fig. 12. TFEB prevents diet-induced obesity and metabolic syndrome. Total serum insulin, leptin, triglyceride and cholesterol levels in control and HDAd-TFEB mice kept on high-fat diet (HFD) for 10 weeks. Values are mean ± sd. n=10. *P<0.05; ****P<0.0001 compared to control. Fig. 13. TFEB rescues the metabolic syndrome in Ob/Ob mice. Total serum glucose (a), insulin (b), and cholesterol (c) levels in Ob/Ob and Ob/Ob+HDAd-TFEB mice. Plasma triglyceride (d) fractions were analyzed by fast performance liquid chromatography (FPLC). e, glucose tolerance tests in Ob/Ob and Ob/Ob+HDAd-TFEB mice. Glucose levels were measured before and at the indicated time points after glucose challenge. Values are mean ± sd. n=5, *P<0.05.
Fig. 14. TFEB overexpression increases the expression level of both autophagy/lysosomal and lipid metabolism genes. mRNA levels of the indicated genes were quantified by qRT-PCR in total RNA isolated from liver samples of mice infected with HDAd-TFEB virus. GAPDH was used as a control gene.Values are mean for n=3 and are expressed as fold increase compared to control mice (injected with transgeneless viral vector)
Fig. 15. Regulatory overlap between starvation response and TFEB overexpression in liver. Genes involved in lipid metabolism represent 9% and 21% of the differentially-expressed genes in the overTFEB and WT starved microarray datasets, respectively. The Venn diagram shows that 52 of the lipid metabolism genes are overlapping from the two datasets. Of those, the majority (93%) of the catabolic lipid genes are upregulated, while the majority (80%>) of the anabolic lipid genes are downregulated. Fig. 16. TFEB coordinates the liver starvation response. Starvation induces TFEB nuclear translocation through the inhibition of mTORCl -mediated TFEB phosphorylation. Once in the nucleus, TFEB activates lysosomal and autophagy genes, a process that induces lipophagy and the generation of FFA. TFEB also independently controls the oxidation of FFAs in mitochondria and peroxisomes through the direct regulation of PGC 1 a and PPARa genes
Fig. 17. Table V: list of 124 genes (out of 1384 differential expressed genes, GSE35015) with a known role in lipid metabolic process. For each gene, the specific lipid breakdown or lipid biosynthesis sub-category and the signed ratio (Fold Change >1.5; GSE35015) have been reported. The genes up -regulated and down-regulated are highlighted in red and in green, respectively. The presence of CLEAR sites (consensus TFEB target sites) in the promoter region of the genes has been reported (Yes). The asterisk (*) indicates the genes mapped in a specific sub-category as assessed by literature (Gachon, F. et al. Proline- and acidic amino acid- rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor alpha (PPARalpha) activity. Proc Natl Acad Sci U S A 108, 4794-4799, (2011). Abu-Elheiga, L., Oh, W., Kordari, P. & Wakil, S. J. Acetyl-CoA carboxylase 2 mutant mice are protected against obesity and diabetes induced by high- fat/high-carbohydrate diets. Proc Natl Acad Sci U S A 100, 10207-10212, (2003). Glatz, J. F., Luiken, J. J., van Bilsen, M. & van der Vusse, G. J. Cellular lipid binding proteins as facilitators and regulators of lipid metabolism. Mol Cell Biochem 239, 3-7 (2002). Hyder, A., Zenhom, M., Klapper, M., Herrmann, J. & Schrezenmeir, J. Expression of fatty acid binding proteins 3 and 5 genes in rat pancreatic islets and INS- IE cells: regulation by fatty acids and glucose. Islets 2, 174-184, (2010). Steenbergen, R., Nanowski, T. S., Nelson, R., Young, S. G. & Vance, J. E. Phospholipid homeostasis in phosphatidylserine synthase-2- deficient mice. Biochim Biophys Acta 1761, 313-323, (2006). Suh, J. M. et al. Adipose is a conserved dosage-sensitive antiobesity gene. Cell Metab 6, 195-207, (2007). Engelking, L. J. et al. Schoenheimer effect explained—feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J Clin Invest 115, 2489-2498, (2005). Koo, S. H. et al. PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med 10, 530-534, (2004). Tomsig, J. L. et al. Lipid phosphate phosphohydrolase type 1 (LPP1) degrades extracellular lysophosphatidic acid in vivo. Biochem J 419, 611-618, (2009).
Fig. 18. Table VI: list of 162 probesets corresponding to the 132 genes differentially expressed both in WT starved microarray dataset (GSE36510) and in the liver microarray dataset following TFEB overexpression (GSE35015).
Fig. 19. Table VII: list of 52 genes with a known role in lipid metabolism. The 52 genes represent the 39% of the genes differentially expressed (refer to Supplementary Table 4) both in the liver microarray dataset following TFEB overexpression (overTFEB; GSE35015) and in the WT starved microarray dataset (GSE36510). For each gene, the specific lipid breakdown or lipid biosynthesis sub-category and the signed ratio (Fold Change >1.5) in the two datasets are reported.
Fig. 20. Table VIII: Lipid Breakdown genes, list of 52 genes with a known role in the different lipid breakdown sub-categories.
Fig. 21. Table IX: Lipid Biosynthesis genes, list of 72 genes with a known role in the different lipid biosynthesis sub-categories.
Fig. 22. Table X: Inflammatory response genes, List of 66 genes with a known role in the inflammatory response
DETAILED DESCRIPTION OF THE INVENTION
Materials and Methods
Generation of mouse models
Tcfeb-fiox (Tcfeb-LiKO) mouse line generation was described previously (5). The transgenic line expressing the CRE under the Albumin promoter (ALB-CRE) was obtained from the Jackson laboratory. All mice were maintained in a C57BL/6 strain background and housed in a temperature-controlled environment with 12 hr light/dark cycles. Fasting experiments were carried for 24h starting from the morning otherwise indicated. For the high fat diet study, age- matched male mice had free access to water and were fed ad libitum a Western-style diet (Harlan Teklad TD 88137) containing 21% (w/w) total lipid (42% calories as anhydrous milk fat). Body weights were recorded bi-monthly. At the end of the feeding period, mice were euthanatized prior to organ harvest. For all experiments involving TcFEB-LIKO mice, the control mice were TcFEB loxP/loxP mice that did not have the Albumin Cre transgene. All experiments were approved by the Committee on Animal Care at the Baylor College of Medicine and conform to the legal mandates and federal guidelines for the care and maintenance of laboratory animals. HP Ad virus production
HDAd-TFEB containing hTFEB expression cassette was composed of the following elements (from 5' to 3'): a liver-restricted rat phosphoenolpyruvate carboxykinase promoter (16), the ApoAI intron, the hTFEB cDNA, the woodchuck hepatitis virus posttranscriptional regulatory element, the ApoE locus control region, and the human growth hormone poly(A). HDAd was produced in 116 cells with the helper virus AdNG163 as described in detail elsewhere (77, 18). Characterization of the vector revealed the expected genomic structure and a level of helper virus contamination of 0.05%> as previously described (17). Hepatic transduction was achieved by intravenous administration (retro-orbital) of approximately 400ml corresponding to 1013 Viral particle/kg. For the HDAd-TFEB injected mice only inbred C57BL/6 male mice were used. As control for this experiment the authors used age sex matched mice infected with 1013 viral particle/kg transgeneless HDAd vector.
Histology and Electron Microscopy
For staining of mouse liver sections, mice were injected intraperitoneally with 20 mg/mL Avertin and then subjected to intracardial perfusion using 4% paraformaldehyde (PFA) in PBS. Liver were dissected and post-fixed with buffered 4% PFA overnight at 4°C, then washed with PBS and cryoprotected in successive sucrose solutions diluted with PBS: 5% for 30 minutes, 10% for several hours, and 20% overnight at 4°C; finally embedded in OCT. Cryostat sections were cut at 10mm. Hematoxylin/eosin and Oil red O staining protocols were performed following the IHC world protocols (http://www.ihcworld.com). Ultra-thin sections of approximately 70nm were obtained using an RMC MT6000-XL ultramicrotome and a Diatome Ultra45 diamond knife, and collected on 150 hex-mesh copper grids. The ultra-thin sections were then stained with Reynold's lead citrate for 4 minutes. The air-dried samples were examined on a Hitachi H7500 transmission electron microscope and images were captured using a Gatan US 1000 digital camera and Digital Micrograph vl .82.366 software.
Glucose tolerance test, insulin tolerance test and pyruvate tolerance tests
For GTT, mice were injected with glucose (1.5 mg/g body weigh) after 6 h fasting. For ITT, 4h fasted mice were injected (i.p.) with insulin (0.75 milliunit/g body weight, Humulin R; Eli Lily). Experiments were performed between 10 AM and 12 PM. Blood was taken before and 15, 30, 60, and 120 min after treatment for determination of glucose and insulin levels. For the pyruvate tolerance test, following an 16-h fast, mice received an i.p. injection 2 g/kg of sodium pyruvate (Sigma) dissolved in PBS. Blood glucose concentrations were measure via tail bleed before and at times indicated after injection.
Tissue lipid quantification
Liver triglycerides, free fatty acids, and cholesterol were extracted as follows: Briefly, pulverized liver was homogenized in PBS, then extracted using chloroform/methanol (2: 1), dried overnight and resuspended in a solution of 60% butanol 40% Triton X-l 14/methanol (2: 1). Measurements normalized to protein content in initial homogenate by DC Protein assay (Bio-Rad).
Plasma chemistry analysis
The authors collected blood from the orbital plexus under isoflurane (Vedco) anesthesia. Plasma was frozen in aliquots at -20°C or used immediately after collection. The authors used enzymatic kits for determination of serum NEFA, ketone bodies (Wako), glycerol (Sigma Aldrich), cholesterol, and TG (Infinity). Plasma glucose was monitored by glucometer and insulin was measured by ELISA (Mercodia). For the TG clearance assay mice were fasted for 24 hours. 250 ul of Intralipid was administered by oral gavage and tail blood was collected at the indicated time.
Body composition analysis
Whole body compositions of mice were analyzed by EchoMRI (Echo Medical Systems) according to the manufacturer's instructions.
Fatty acid oxidation measurement
The increased oxygen consumption rate (OCR) following BSA-conjugated palmitate addition was measured using the XF24 extracellular flux analyzer (Seahorse Bioscience) following manufacturer instruction.
In vivo metabolic analysis
Analysis of oxygen consumption (V02) carbon dioxide (C02) and respiratory exchange ratio (RER) was performed using the Oxymax Columbus Instruments Comprehensive Lab Animal Monitoring System; mice were acclimatized to the system for 24 hr prior to data collection. All the data were normalized to weight. Rates of carbohydrate (4.58*VC02 - 3.23*V02) and fat (1.70*VO2 - 1.69*VC02) utilization were calculated as previously described (19, 20).
Primary hepatocvte culture
2-month-old mice were deeply anaesthetized with Avertin (240 mg/kg) and perfused first with 25 ml of HBSS (Sigma H6648) supplemented with lOmM HEPES and 0.5mM EGTA and after with a similar solution containing 100 U/ml of Collagenase (Wako) and 0.05 mg/ml of Trypsin inhibitor (Sigma). Liver was dissociated in a petri dish, cell pellet was washed in HBSS once and in 50% percoll gradient (Perkin Helmer) and plated at density of 5* 105 cells/35mm dish. Cells were cultured in William's medium E supplemented with 10%FBS, 2mM glutamine, 0.1 mM Insulin, 1 mM Dexamethasone and pen/strep. For the starvation experiments, 24h after preparation, cells were incubated with HBSS (+ CaCl2 and MgS04; GIBCO) supplemented with 1 OmM HEPES (GIBCO) and cultured for 24h prior harvesting.
RNA extraction, quantitative PCR, and statistical analysis
Total RNA was first extracted from cells using TRIzol (Invitrogen) and then re-purified with RNeasy column (Qiagen). Reverse transcription was performed using TaqMan reverse transcription reagents (Applied Biosystems). Lysosomal and autophagic gene-specific primers were previously reported (5). Lipid metabolism gene-specific primers are listed in Table I. Fold change values were calculated using the DDCt method as previously reported (5).
Unpaired T-Test was used to calculate statistical significance.
Bioinformatics and data visualization
Venn diagrams and pie charts were generated using custom annotation scripts.
Microarray hybridization Total RNA (3 μg) was reverse transcribed to single-stranded cDNA with a special oligo (dT) 24 primer containing a T7 RNA promoter site, added 3' to the poly-T tract, prior to second strand synthesis (One Cycle cDNA Synthesis Kit by Affymetrix, Fremont, CA, USA). Biotinylated cRNAs were then generated, using the GeneChip IVT Labeling Kit (Affymetrix). Twenty micrograms of biotinylated cRNA was fragmented and 10 μg hybridized to the Affymetrix GeneChip Mouse 430A 2 microarrays for 16 hours at 45°C using an Affymetrix GeneChip Fluidics Station 450 according to the manufacturer's standard protocols. For the analysis of the injected mice overexpressing TFEB, total RNA was extracted from the liver of three mice. RNA extracted from the liver of 3 not-injected mice was used as a control. For the analysis on the starved mice (24hrs), total RNA was extracted from the liver of two wt mice; RNA extracted from the liver of two wt mice was used as control.
Microarray data processing
The data discussed in this publication have been deposited in NCBIs Gene Expression Omnibus (GEO) (2i)and are accessible through GEO Series accession number GSE35015 (overTFEB dataset) and GSE36510 (WT starved dataset). Low-level analysis to convert probe level data to gene level expression was performed using Robust Multiarray Average (RMA) implemented using the RMA function of the Bioconductor project (22).
Statistical analysis of differential gene expression
For each gene, a Bayesian t-test (Cyber-t) (2J)was used on RMA normalized data to determine if there was a significant difference in expression between mice overexpressing TFEB (injected mice) versus not-injected mice used as control (GSE35015 - overTFEB dataset); the same analysis was repeated to compare expression in starved wt mice versus wt mice (GSE36510 - WT starved dataset). P-value adjustment for multiple comparisons was done with the False Discovery Rate (FDR) of Benjamini-Hochberg(24). The threshold for statistical significance chosen was FDR<0.05; a further filtering was performed by selection genes with an absolute Fold Change >1.5 for both increased (up-regulated genes) and decreased (down-regulated genes) expression levels. In the overTFEB dataset the authors selected 1814 probesets corresponding to 1384 differentially expressed genes (GSE35015). The expression levels of 773 genes, out of 1384, were significantly increased, while the expression levels of the remaining 61 1 genes were significantly decreased. In the WT starved dataset the authors selected 467 probesets corresponding to 370 differentially expressed genes (GSE36510). The expression levels of 163 genes, out of 370, were significantly increased, while the expression levels of the remaining 207 genes were significantly decreased.
Microarray data analysis For each microarray dataset, the Gene Ontology Enrichment Analysis (GOEA) (£ Iff) was performed on the up-regulated and down-regulated gene lists, separately, by using the DAVID online tool (DAVID Bioinformatics Resources 6.7) restricting the output to all Biological Process terms (BP ALL) (refer to Table II and Table III for the overTFEB dataset; refer to table IV for the 132 genes differentially expressed both in WT starved and in overTFEB datasets listed in table VI). The threshold for statistical significance of GOEA was FDR<10% and Enrichment Score >1.5. To obtain the Figure 1 , the list of 1814 probesets (GSE35015) was mapped on the GO hierarchy (25, 26) rooted in the Lipid Metabolic Process (GO:0006629) term. The authors considered the "children" of the two main sub-categories of the Lipid Metabolic Process: the lipid catabolic process (GO: 0016042) and the lipid biosynthetic process (GO:0008610). The lipid catabolic process (GO:0016042) contains 6 sub-categories, while the lipid biosynthetic process (GO:0008610) contains 15 sub-categories. The cellular lipid catabolic process (GO:0044242), which is one of the "children" of the lipid catabolic process, was divided in its 7 sub-categories for the analysis. The two "children" of the lipid oxidation (GO:0034440) were also analyzed. The authors introduced one more sub-category, the fatty acid binding and transport, to map genes as indicated in literature. The 1384 differentially expressed genes were mapped to 20 sub-categories (http://www.geneontology.org/ (25, 26)): 7 sub-categories of the lipid catabolic process, 1 1 sub-categories of the lipid biosynthetic process, 1 sub-category of the lipid oxidation and the fatty acid binding and transport. The total number of the mapped genes was 124 (table V). The distribution of these genes among the 20 sub-categories was visualized in Cytoscape, an open source platform for complex network analysis and visualization (27). The threshold for statistical significance chosen for the comparison between the overTFEB dataset and WT starved dataset was FDR<0.05 and absolute Fold Change >1.5 : the authors thus selected 162 probesets corresponding to 132 differentially expressed genes (table VI). In detail, the authors found that the expression levels of 48 and of 53 genes were significantly increased and decreased, respectively, in both datasets, while the expression levels of the remaining 31 genes were significantly regulated in opposite manner in the two datasets. The GOEA on the list of 132 genes was performed as described above and reported in table IV.
The total number of the genes, out of 132, mapped to the different Lipid Metabolic Process sub- categories was 52 (table VII). The complete list of 77 genes with a known role in lipid metabolism differentially expressed in WT starved microarray dataset is not shown.
Chromatin immunoprecipitation
Mice overexpressing TFEB-FLAG in liver were previously described (5). As control were used transgeneless littermate. The liver was isolated from 5 days old mice and incubated in 1% formaldehyde for 10 minutes at room temperature to cross-link DNA to associated proteins. The tissue was washed twice with ice-cold phosphate buffered saline (PBS) containing 0.125 M glycine and protease inhibitors (PI; complete protease inhibitor cocktail tablets, Roche Applied Science, Indianapolis, IN) and then homogenized in lysis buffer (10 mM Tris-HCl pH 7.5, 10 mM NaCl, 3 mM MgC12, 0.5% NP40) containing PI. After 10 minutes of incubation on ice, the lysate was centrifuged for 5 minutes at 3,000 rpm and 4°C, and the nuclear pellet was sonicated with a Branson Sonifier 450 for 6 seconds at power level 6. The homogenate was then digested with 300 U of micrococcal nuclease for 5 minutes at 37°C (Worthington Biochemical Corporation, Lakewood, NJ) to generate fragments with an average length of -100-200 bps, as determined empirically by agarose gel electrophoresis of the fragmented chromatin sample. For immunoprecipitation, 200 μΐ of chromatin was diluted 1 : 10 in ChIP dilution buffer (Millipore Corporation, Billerica, MA) and 1% of the diluted sample was set aside for input. The sample was precleared with streptavidin beads (Thermo scientific) at 4°C for 3 hours. The precleared lysate was incubated overnight ^g of biotinilated anti-Flag antibody (BioM2 SIGMA). After immunoprecipitation, the beads were washed at room temperature (for 5 minutes each) with 700 μΐ of low salt buffer, high salt buffer, LiCl buffer (Millipore Corporation, Billerica, MA), and TE buffer (10 mM Tris-HCl pH 7.4, 1 mM EDTA pH 8.0). Elution was performed twice in 250 μΐ of fresh elution buffer (1% SDS, 0.1 M NaHC03) for 15 minutes at room temperature. The eluates were combined, 20 μΐ of 5 M NaCl was added, and samples were incubated overnight at 65 °C to reverse the crosslinks. The input DNA was diluted in freshly made elution buffer to a volume of 500 μΐ, and cross-link reversal was performed. After cross-link reversal, samples were digested with 20 μg of proteinase K for 1 hour at 55°C, and DNA was recovered by standard methods in 30 μΐ of 10 mM Tris-HCl pH 8.0. One μΐ of DNA was used for each quantitative real-time PCR. The quantitative real-time PCR data were analyzed as follows: Relative proportions of immunoprecipitated DNA were determined based on the threshold cycle (Ct) value for each PCR reaction. In order to control for variation between ChIP fractions, for every gene promoter studied, a ACt value was calculated for each sample (WT, TFEB-FLAG) by subtracting the Ct value for the input (Ctlnput) from the Ct value for the immunoprecipitated sample (Ctantibody). Because the input DNA fraction represents only 1% of the total material (see above), the Ctlnput value was first adjusted for this dilution factor by subtracting 6.644 cycles (Log2 of 100). The formula used was: ACt = [Ct elute - (Ctlnput - 6.644)]. Next, a AACt value was calculated for each sample by subtracting the ACt WT (transgeneless) from the corresponding ACt (transgene). Fold differences between the specific immunoprecipitation and the background were then determined by raising 2 to the -AACt power. Primers are listed in Table I.
Table I: List of primers Primers used for quantitative PCR Primers used for Cftromattne Immunoprecipitation
Acot2 F AAGAAGCCGTGAACTACCTGCG CD36 TCACTCACACACGGCAAAAT
Acot2 R TGTGATGCCCTTCAGGAAGGAG CD36 GCCAGATGCTTGGTCAAATC
CRAT F AGAGCCTGTTGGCATCCTAACC PGC!a GGGTGTTGCCTTCAAACACT
34
CRAT R TTGTCCAGGCACACGGTGAAGA 1 D PGCIa CAAGTAGCCCCAGACTCAGC
Mogai 2 F CACGGGCTTTACCTCGCI 1 IC ID PGCIa GAAAGAAAATCGGGGGTGTT
Mogat 2 R CCTGGACAGAATGTGATCGGCA PGCIa CAAGTAGCCCCAGACTCAGC
ApoA4 F CAGAAGACGGATGTCACTCAGC ID PGC Ia TGACAGCCCAGCCTAC 1 1 i 1 ID
ApoA4 R AGCTGTACGACAAAGGGCACCA PGCIa CCAGCCCCTTACTGAGAGTG
Cyp7a1-F CACCATTCCTGCAACCTTCTGG PGCIa AAAAGCTTGACTGGCGTCAT
Cyp7a1-R ATGGCATTCCCTCCAGAGCTGA PGCIa CCCCAGCTCACCTCTATGTC
Ppar « -F AC CACT AC G GAGTTCACG CATG HADH CTTCAAAGGGAGTGCAGGAG
Ppar -R GAATCTTGCAGCTCCGATCACAC HADH ATTGTTTCCATGCCTGTTCC
Ppargc- -F GAATCAAGCCACTACAGACACCG HADH AAAACATAGCCCCTGCTTCA
Ppargc o-R CATCCCTCTTGAGCCTTTCGTG HADH GCTCCATGTCCTCCTCTTCC
Cptla-F GGCATAAACGCAGAGCATTCCTG HADH GATGACGGTCACATGCTTGA
Cptl a-R CAGTGTCCATC CTCTG AGT AGC Cyp7a1 TAGCTGTTGTCC CCAGCTTT
Fabp -F TGAAATCACCGCAGACGACAGG Cyp7a1 AAGAGGCTCCAGAACAAGCA
Fabp4-R GCTTGTCACCATCTCG M i l CTC Cyp7a1 TTGTCCCCAGCTTTGAATGT
Hmgcs l F GGAAATGCCAGACCTACAGGTG Fabp3 AGCCCCGGCTTCCTATTT ID
Hmgcs l-R TACTCGGAGAGCATGTCAGGCT Fabp3 GAGTGAGGAGGCGAGCAG
Hmgcs2-F TGCTATGCAGCCTACC GCAAG A Fabp3 CGGCTGGACAGCCTCTTTA
Hmgcs2-R GCCAGGGATTTCTGGACCATCT Fabp3 ATGTGATGCGAGGGCTATTT
Cyp39a1-F CTACTTCATGGCATTTGGAGGCG Fabp3 AAGTCACTCGGTGAGCGAAC
Cyp39a1-R GGTAATGGGTCCAGAAGACTGC Fabp3 CTGGACTGGCTAGGAGCTTG
pPARa TGGCATAGCACACATTTCGT
pPARa GCTTTGCTTGTGTCGTCCTT
pPARa TGGCATAGCACACATTTCGT
pPARa TCTTCAGTCACGGAATGCAC
pPARg TGCACTGCCTATGAGCACTT
pPARg TGTGGAAAACAAACATGCAA
pPARg AACATGCAATTTCACCCACA 61
Results
To study the physiological role of TFEB the authors generated transgenic mice that specifically lack TFEB in the liver (Tcfeb- iKO), a primary player in the starvation response.
The liver from Tcfeb- iKO mice displayed a striking increase in lipid droplets after a 24h starvation, compared to wild type littermates, suggesting a defect in intracellular lipid degradation (Fig. 1A,B and Fig. 7). This was supported by a significant decrease in the degradation rate of an exogenously added fatty acid (i.e. palmitate) in Tcfeb-LiKO hepatocytes, demonstrating an impairment of free fatty acid (FFA) oxidation (Fig. 1C). During starvation, peripheral lipolysis generates FFAs that are subsequently oxidized in the liver. This results in the production of acetyl-CoA, the building block of ketone bodies. Consistent with a defect of FFA oxidation, Tcfeb- iKO mice showed decreased plasma levels of circulating ketone bodies after 24h-starvation compared to control mice (Fig. ID). The possibility that this was due to an impairment in FFA uptake by the liver was excluded by the normal levels of circulating FFA during starvation and the normal uptake of exogenously administered FFA in Tcfeb- iKO mice (Fig. 8). Notably, the starvation-induced depletion of fat body mass was impaired in Tcfeb- iKO mice compared to controls, whereas the depletion of lean mass was unchanged, as a secondary consequence of an impaired fat breakdown by the liver (Fig. IE). No differences in gluconeogenic rate were observed between Tcfeb- iKO and control mice (Fig. 9). Together these data strongly suggest that TFEB controls the liver response to starvation by regulating the rates of FFA oxidation and ketogenesis.
To study whether TFEB is sufficient to drive a starvation response in the liver the authors generated a helper-dependent adenoviral vector that expresses the human TFEB cDNA (HDAd- TFEB, Fig. 6) under the control of a liver-specific promoter and enhancer (6) and injected it retro-orbitally into 5 weeks old C57BL/6 mice. This resulted in a robust expression of TFEB selectively in the liver, which lasted for the entire length of the experiments (i.e. 4 months) (Fig. 10). When fed with a regular chow diet, HDAd-7FE5-injected mice were significantly leaner than controls (Fig. 2A), with a decreased deposition of body fat (Fig. 2B). Conversely, Tcfeb- LiKO mice showed an increase in peripheral adiposity but no significant changes in body weight compared to controls (Fig. 2A,B). In addition, HDAd-7FE5-injected mice had lower plasma levels of total cholesterol and triglycerides, associated with a reduction of VLDL, while HDL was largely unaffected (Fig. 2C-F). HDAd-7FE5-injected mice also showed lower levels of circulating leptin, insulin and glucose, and higher levels of adiponectin (Fig. 2G-J). The levels of these serum parameters in Tcfeb- iKO mice showed no differences compared to controls (Fig. 2C, D, G-J). Overall the phenotype observed in HDAd-7FE5-injected mice was similar to that observed in mice that undergo caloric restriction (7), although no differences in food intake were observed between HDAd-7FE5-injected and wild type mice (Fig. 1 1). These results suggest that TFEB overexpression mimics caloric restriction by enhancing nutrient metabolism independently of food intake. Indeed, indirect calorimetric analysis demonstrated increased energy expenditure in HDAd-7FE5-injected mice compared to controls (Fig. 2K,L). Notably, HDAd-7FE5-injected mice also showed a decrease in respiratory exchange rate (RER) (Fig. 2M), an increase in the FFA oxidation rate (Fig. 2N) and no changes in carbohydrate oxidation (Fig. 20), further supporting the presence of an enhanced fat catabolism.
These observations prompted us to test the metabolic effects of TFEB gain- and loss-of-function in mice challenged with high-fat diet. The authors found that Tcfeb- iKO mice gained substantially more weight than control littermates when challenged with a high-fat and high- cholesterol "western" diet for three months (Fig. 3A), even though the two types of mice had a similar food intake (Fig. 11). Conversely, TFEB overexpression in HDAd-7FE5-injected mice both prevented and blocked diet-induced obesity (Fig. 3A), in spite of a slight increase in food intake compared to control mice (Fig. 11). Body composition analysis revealed that the weight difference between TFEB gain- and loss-of-function mice was largely due to differences in fat accumulation, which was higher in Tcfeb- iKO and lower in HDAd-7FE5-injected mice compared to controls (Fig. 3B). Striking differences were observed in liver appearance and lipid content in the different types of mice when fed with a high-fat diet. The liver from Tcfeb- iKO mice was large, pale and filled with lipid vacuoles. Control mice fed with the same diet showed a similar, albeit milder, phenotype. Conversely, the liver from HDAd-7FE5-injected mice had normal reddish color, markedly reduced lipid content, and normal weight, suggesting that TFEB overexpression rescued the effects of the high-fat diet (Fig. 3C-E). Of note, the abnormalities of the serum metabolic profile induced by the high-fat diet in wild-type mice, which were characterized by an increase of circulating leptin, insulin, triglycerides and cholesterol, were markedly attenuated in HDAd-7FE5-injected mice (Fig. 12), which also showed an improved sugar metabolism, as demonstrated by glucose and insulin tolerance tests (Fig. 3F-H).
Similar experiments were performed in a genetic model of obesity due to leptin deficiency (Ob/Ob), which is associated with hyperphagia (8). Two-months-old Ob/Ob mice, which at this age were already obese, were injected with HDAd-TFEB. Six weeks later HDAd-7FE5-injected Ob/Ob mice had similar weight but significantly reduced levels of circulating triglycerides, cholesterol, glucose and insulin and improved glucose tolerance test, compared to untreated Ob/Ob mice, indicating that TFEB overexpression in liver improved the metabolic syndrome phenotype independent from its effect on body weight (Fig. 13).
To understand how TFEB regulated lipid metabolism, the authors performed liver transcriptome analysis following TFEB overexpression. Gene expression profiling experiments, performed four weeks after HDAd-TFEB injection, revealed that TFEB overexpression perturbed the mouse liver transcriptome in a statistically-significant manner. The expression levels significantly increased in 773 genes and decreased in 611 (GSE35015). The results of microarray analyses were validated by quantitative realtime PCR (qPCR) of 46 genes (Fig. 14). Gene Ontology Enrichment Analysis (GOEA) revealed that the gene category most significantly up-regulated by TFEB overexpression was the cellular lipid metabolic process, which includes monocarboxylic acid, fatty acid, and cellular ketone metabolic processes, among others (Table II) (£ 10).
Conversely, the authors observed that several gene categories related to lipid biosynthesis, such as steroid, lipid and isoprenoid biosynthetic processes were significantly down-regulated (Table III). As expected, TFEB also positively regulated the expression of several genes involved in lysosome organization and autophagy (Table II and Fig. 14), consistent with previous results (3, £ IP). The global control exerted by TFEB on lipid metabolism is illustrated in Figure 4A and Table V, Fig. 17. The TFEB lipid metabolism network includes genes involved in several steps of lipid catabolism, which occur in different cellular compartments, such as the transport of fatty acid chains across the plasma membrane (e.g. CD36 and FABPs) and the β-oxidation of FFA in mitochondria (e.g. Cptl,Crat, Acadl Acads, Hdad) and peroxisomes (Cyp4a genes).
Consistent with a role of TFEB as a main mediator of the starvation response, the authors found that the transcriptomic signature of TFEB overexpression in the liver was similar to that of starvation (GSE36510 and Table VI, Fig. 18), particularly for genes involved in lipid metabolism (Fig. 15, Table IV and Table VII, Fig. 19). Surprisingly, very few of these genes showed the presence of the consensus TFEB binding sequence (i.e. the CLEAR site) (11), in their promoters (Table V, Fig. 17), suggesting that the regulation of lipid metabolism by TFEB may be mediated by other factors. Interestingly, some of the pathways induced by TFEB overexpression in the liver, such as upregulation of lipid breakdown, downregulation of lipid biosynthesis, and downregulation of inflammatory response (Tables II, III and V, Fig. 17 and Tables VIII-X, Fig. 20-22), resemble those induced by PGCla (Ppargcla) and PPARa (Ppara), two key regulators of lipid metabolism that are activated during starvation (12-15).
The authors found that both PGCla and PPARa were significantly upregulated upon TFEB overexpression (Fig. 4a, Table I, Table V, Fig. 17). In addition, the upregulation of PGCla and of PGCla and PPARa target genes, during starvation was significantly blunted in Tcfeb- iKO mice compared to controls (Fig. 4B). A similar result was observed in cultured hepatocytes, where the authors observed that the absence of TFEB suppressed, while TFEB overexpression enhanced, the effects of starvation on the expression of PGCla and PPARa target genes (Fig. 4C).
Table II: Complete list of BPs related to the GOEA for the genes significantly up-regulated (773 genes in total) in the liver microarray dataset following TFEB overexpression (GSE35015). The data in this table were collected by using the DAVID online tool restricting the output to BP ALL terms.
Table III: complete list of BPs related to the GOEA for the genes significantly down-regulated (611 genes in total) in the liver microarray dataset following TFEB overexpression (GSE35015). The data in this table were collected by using the DAVID online tool restricting the output to BP ALL terms.
Table IV: complete list of BPs related to the GOEA for the 132 genes differentially expressed both in WT starved and in overTFEB datasets (refer to Table VI). Table II
Figure imgf000027_0001
AI132487, JUB, GRPEL2, GNPDA1, AQP8, RASL2-9, AQP7,
AQP1, WNT2, APOA4, STAR05, SLC2A2, KIFAP3, ATG7,
CNKS, MCOLN1, HBB-B1, HBB-B2, SLC4A4, SGPL1, Y06,
MFGE8, VPS41, TCN2, IRS1, GLTP, SLC25A30, HHEX,
PITPNMl, IGHG, AAAS, NNT, CD36, ABCBIA, RAB17, CAMK1,
SLC40A1, VPS26A, ARL6IP1, MY09B, ATP6V0C-PS2,
ATP6V1B2, ATP6V0B, CD74, ATP6V0C, SLC31A2, GABRD,
LAPTM4B, MRC1, OSBPL5, MSTOl, TGFBR2, DENND1A,
GOLIM4, CRAT, KITL, KCNK3, ABCG2, KDR, P2RX4, LYVE1,
TSC1, NDUFV1, TOMM40L, KCTD17, SYTL4, FABP3,
2010001E11RIK, FABP2, FABP5, SLC45A3, SLC20A1, SLC15A2,
G0TER _
GO:0051179~localization 152 2,34E-05 BCAR1, HEXA, ZMAT3, HEXB, PPARG, HPS4, 2EB2, AMN, 0,041352627 BP ALL AP2B1, SLC1A2, DYNLL2, AI317395, NDUFS1, CLN3, RAMP2,
PTGER3, SLC25A4, SLC25A5, CYCS, SLC24A6, TIMM44, MFN2,
ANKRD27, ATP6V1A, G6PC, IGF2R, CD81, OSBPL11, SNX12,
CLN8, MY05A, VPS29, BID, ATG10, FTL1, RAB3D, FTL2, FUT8,
SNX16, LOC434624, MFSDl, KIT, SEC14L2, TPCNl, CCL25,
SLC01A4, TMED4, RAB43, SORBS1, GNPTAB, SLC35B4,
SLC39A8, CAMK2D, SLC25A42, CAR2, GLRX, TES, TXNIP,
CPT1B, ABCA8B, ABCA8A, FADS2, STAB2, CPT1A, PLEKHF1,
SLC01B2, HBA-A1, HBA-A2, SLC16A2, RAB30, SLC16A7,
FCGR2B, FYN, SLC6A8, BAX, RAB34, SLC6A6, ABCC3, SLC18A1,
CTNS, SNX30, APBB1, GGA2, LRP4
AI132487, GRPEL2, GNPDA1, AQP8, RASL2-9, AClP7, AQP1,
WNT2, APOA4, STARD5, SLC2A2, ATG7, KCNK5, MCOLN1,
HBB-B1, HBB-B2, SLC4A4, MY06, MFGE8, VPS41, TCN2, IRS1,
GLTP, SLC25A30, PITPNMl, IGHG, CD36, NNT, AAAS, ABCBIA,
RAB17, CAMK1, SLC40A1, VPS26A, ARL6IP1, MY09B,
ATP6V0C-PS2, ATP6V1B2, ATP6V0B, CD74, ATP6V0C,
SLC31A2, GABRD, LAPTM4B, MRC1, OSBPL5, TGFBR2,
DENND1A, GOLIM4, CRAT, KCNK3, ABCG2, P2RX4, LYVE1,
TSC1, NDUFV1, TOMM40L, KCTD17, SYTL4, FABP3,
2010001E11RIK, FABP2, FABP5, SLC45A3, SLC20A1, SLC15A2,
GOTER _
GO:0006810~transport 136 3,70E-05 ZMAT3, PPARG, HPS4, AMN, AP2B1, SLC1A2, DYNLL2, 0,06S367824 BP ALL AI317395, NDUFS1, CLN3, RAMP2, PTGER3, SLC25A4,
SLC25AS, CYCS, SLC24A6, TIMM44, MFN2, ANKRD27,
ATP6V1A, G6PC, IGF2R, OSBPL11, SNX12, CLN8, MY05A,
VPS29, BID, ATG10, FTL1, RAB3D, FTL2, SNX16, LOC434624,
MFSDl, SEC14L2, TPCNl, SLC01A4, TMED4, RAB43, GNPTAB,
SORBS1, SLC35B4, SLC39A8, CAMK2D, SLC2SA42, CAR2,
GLRX, TES, TXNIP, CPT1B, ABCA8B, ABCA8A, FADS 2, STAB2,
CPT1A, PLEKHF1, SLC01B2, HBA-A1, HBA-A2, SLC16A2,
RAB30, SLC16A7, FCGR2B, SLC6A8, BAX, RAB34, SLC6A6,
ABCC3, SLC18A1, CTNS, SNX30, GGA2, APBB1, LRP4
AI132487, GRPEL2, GNPDA1, AQP8, RASL2-9, AQP7, AQP1,
WNT2, APOA4, STARD5, SLC2A2, ATG7, KCNK5, MCOLN1,
HBB-B1, HBB-B2, SLC4A4, MY06, MFGE8, VPS41, TCN2, IRS1,
GLTP, SLC25A30, PITPNMl, IGHG, CD36, NNT, AAAS, ABCBIA,
RAB17, CAMK1, SLC40A1, VPS26A, ARL6IP1, MY09B,
ATP6V0C-PS2, ATP6V1B2, ATP6V0B, CD74, ATP6V0C,
SLC31A2, GABRD, LAPTM4B, MRC1, OSBPL5, TGFBR2,
DENND1A, G0LIM4, CRAT, KCIMK3, ABCG2, P2RX4, LYVE1,
TSC1, NDUFV1, TOMM40L, KCTD17, SYTL4, FABP3,
2010001E11RIK, FABP2, FABP5, SLC45A3, SLC20A1, SLC15A2,
GOTER _ GO:0051234~establishment
136 5.29E-05 ZMAT3, PPARG, HPS4, AMN, AP2B1, SLC1A2, DYNLL2, 0,093302371 BP_ALL of localization
AI317395, NDUFS1, CLN3, RAMP2, PTGER3, SLC25A4,
SLC25A5, CYCS, SLC24A6, TIMM44, MFN2, ANKRD27,
ATP6V1A, G6PC, IGF2R, OSBPL11, SNX12, CLN8, MY05A,
VPS29, BID, ATG10, FTL1, RAB3D, FTL2, SNX16, LOC434624,
MFSDl, SEC14L2, TPCNl, SLC01A4, TMED4, RAB43, GNPTAB,
SORBS1, SLC35B4, SLC39A8, CAMK2D, SLC2SA42, CAR2,
GLRX, TES, TXNIP, CPT1B, ABCA8B, ABCA8A, FADS 2, STAB2,
CPT1A, PLEKHF1, SLC01B2, HBA-A1, HBA-A2, SLC16A2,
RAB30, SLC16A7, FCGR2B, SLC6A8, BAX, RAB34, SLC6A6,
ABCC3, SLC18A1, CTNS, SNX30, GGA2, APBB1, LRP4
Annotation Enrichment Score:
Cluster 3 4.416092235868629
Gene
Category Term PValue Genes FDR
Count CYB5R3, LDHB, PPARA, GNPDAl, CHKB, PGAMl, OGDH,
NAGK, AKR1A4, GALK1, INSIG2, CYP7A1, MTPN, PCYT1A,
GOTERM_ GO:0006066~alcohol PDHAl, PPAP2A, GPD2, PDK1, DDC, PDK2, MOGAT2, WDTC1,
45 1,51E-10 2,67E-07 BP_ALL metabolic process CYP46A1, HKDCl, MAOA, PDK4, FDPS, BPGM, DLAT, FUCA2,
CHPTl, CPTIA, GDPDl, EBPL, RENBP, G6PC, LRAT, PKLR, GYG,
FABP3, LOC100047575, CLN8, COMT1, FABP5, CLN6, XYLB
LDHB, PPARA, GNPDAl, FUT8, PGAMl, ST8SIA3, OGDH,
GO:0044262~cellular NAGK, AKR1A4, GALK1, ST3GAL3, GNPTAB, IDH2, PDHAl,
GOTERM_
carbohydrate metabolic 35 9,63 E-07 GPD2, PDK1, PDK2, MOGAT2, WDTC1, HKDCl, PDK4, CS, 0,001699537 BP ALL
process BPGM, DLAT, FUCA2, CPTIA, ST6GALNAC2, GDPDl, RENBP,
G6PC, ST8SIA4, PKLR, GYG, LOC100047575, FABP5, XYLB
LDHB, PPARA, GNPDAl, FUT8, HEXA, HEXB, PGAMl, ST8SIA3,
OGDH, NAGK, AKR1A4, GALK1, ST3GAL3, GNPTAB, CHST14,
GOTERM_ GO:0005975~carbohydrate IDH2, PDHAl, AI464131, GPD2, PDK1, PDK2, MOGAT2,
43 l,21E-06 0,002134157 BP ALL metabolic process WDTC1, HKDCl, PDK4, CS, CHI3L1, BPGM, DLAT, FUCA2,
CPTIA, ST6GALNAC2, GDPDl, GNS, LYVE1, RENBP, G6PC,
ST8SIA4, PKLR, GYG, LOC100047575, FABP5, CLN6, XYLB
PPARA, LDHB, GNPDAl, PGAMl, NAGK, OGDH, GALK1,
GOTERM_ . GO:0005996~monosaccharide AKR1A4, PDHAl, PDK1, GPD2, PDK2, WDTC1, HKDCl, PDK4,
25 l,47E-06 0,002593838 BP ALL metabolic process BPGM, DLAT, FUCA2, CPTIA, G6PC, RENBP, GYG, PKLR,
LOC100047575, FABP5, XYLB
PDK1, GPD2, PPARA, PDK2, LDHB, WDTC1, GNPDAl, HKDCl,
GOTERM_ GO:0019318~hexose
22 7,89E-06 PDK4, PGAMl, BPGM, DLAT, FUCA2, OGDH, CPTIA, GALK1, 0,013924995 BP ALL metabolic process
G6PC, RENBP, PKLR, GYG, LOC100047575, PDHAl, FABP5
GOTERM_ GO:0016052~carbohydrate LDHB, GNPDAl, HKDCl, HEXB, PGAMl, CHI3L1, BPGM, DLAT,
14 2.90E-05 0,051123476 BP ALL catabolic process OGDH, AKR1A4, G6PC, LYVE1, PKLR, PDHAl
PDK1, GPD2, PPARA, PDK2, LDHB, WDTC1, HKDCl, PDK4,
GOTERM_ GO:0006006~glucose
18 7,63E-05 PGAMl, BPGM, DLAT, OGDH, CPTIA, G6PC, PKLR, GYG, 0,134577884 BP_ALL metabolic process
LOC100047575, PDHAl, FABP5
LDHB, GNPDAl, PGAMl, ATP6V1B2, ATP6V0C-PS2, OGDH,
GO:0006091~generation of
GOTERM_ ATP6V0B, ATP6V0C, IDH2, PDHAl, NDUFS1, GLRX, AC02,
precursor metabolites and 26 l,02E-04 0,179296975 BP_ALL HKDCl, CYCS, CS, FADS2, IDH3B, BPGM, DLAT, PPARGC1A,
energy
IDH3A, ATP6V1A, G6PC, NDUFV1, PKLR, GYG
GOTERM_ GO:0046164~alcohol LDHB, GNPDAl, HKDCl, MAOA, PKLR, PGAMl, BPGM,
11 3,42E-04 0,601960676 BP ALL catabolic process PDHAl, DLAT, OGDH, COMT1
GO:0044275~cellular
GOTERM_ LDHB, G6PC, GNPDAl, HKDCl, PKLR, PGAMl, BPGM, PDHAl,
carbohydrate catabolic 10 8,12E-04 1,423505692 BP_ALL DLAT, OGDH
process
GOTERM_ GO:0046365~monosaccharide LDHB, GNPDAl, HKDCl, PKLR, PGAMl, BPGM, PDHAl, DLAT,
9 0,00170347 2,965134872 BP ALL catabolic process OGDH
GOTERM_
GO:0006096~glycolysis 8 0,00215799 LDHB, HKDCl, PKLR, PGAMl, BPGM, PDHAl, DLAT, OGDH 3,742156722 BP ALL
GOTERM_ GO:0019320~hexose
8 0,00565188 LDHB, HKDCl, PKLR, PGAMl, BPGM, PDHAl, DLAT, OGDH 9,522130905 BP ALL catabolic process
GOTERM_ GO:0006007~glucose
8 0,00565188 LDHB, HKDCl, PKLR, PGAMl, BPGM, PDHAl, DLAT, OGDH 9,522130905 BP ALL catabolic process
Annotation Enrichment Score:
Cluster 4 3.288674064515938
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006665~sphingolipid CLN3, SGPL1, PSAP, HEXA, UGCG, HEXB, KIT, SMPDL3A, BAX,
13 8,19E-06 0,014456714 BP ALL metabolic process PPAP2A, CLN8, GAL3ST1, CLN6
GOTERM_ GO:0006643~membrane lipid CLN3, SGPL1, PSAP, HEXA, UGCG, HEXB, KIT, SMPDL3A, BAX,
13 l,15E-05 0,020361633 BP ALL metabolic process PPAP2A, CLN8, GAL3ST1, CLN6
GOTERM_ GO:0007040~lysosome ATP6V0C, CLN3, TPP1, HEXA, HPS4, HEXB, ATP6V0C-PS2,
8 2,13E-05 0,037683154 BP ALL organization CLN8, CLN6
GOTERM_ GO:0006687~glycosphingolipi
7 8,90E-05 CLN3, HEXA, BAX, HEXB, KIT, GAL3ST1, CLN6 0,157070652 BP ALL d metabolic process
GOTERM_ GO:0006664~glycolipid
7 2,20E-04 CLN3, HEXA, BAX, HEXB, KIT, GAL3ST1, CLN6 0,387553677 BP ALL metabolic process
GOTERM_ GO:0007033~vacuole ATP6V0C, CLN3, TPP1, HEXA, HPS4, HEXB, ATP6V0C-PS2,
8 4,35E-04 0,76508892 BP ALL organization CLN8, CLN6
GOTERM_ GO:0006672~ceramide
8 6,28E-04 CLN3, SGPL1, HEXA, HEXB, PPAP2A, CLN8, GAL3ST1, CLN6 1,102381454 BP ALL metabolic process
GOTERM_ GO:0046519~sphingoid
8 8,83E-04 CLN3, SGPL1, HEXA, HEXB, PPAP2A, CLN8, GAL3ST1, CLN6 1,546885902 BP ALL metabolic process
GOTERM_ GO:0050885~neuromuscular
6 0,01284828 MY05A, CLN3, TPP1, HEXA, HEXB, CLN8 20,41156287 BP ALL process controlling balance
GOTERM_ GO:0001573~ganglioside
3 0,0517718 HEXA, HEXB, CLN6 60,87942986 BP ALL metabolic process
GOTERM_ GO:0050905~neuromuscular
6 0,10550245 MY05A, CLN3, TPP1, HEXA, HEXB, CLN8 86,03156238 BP ALL process Annotation Enrichment Score:
Cluster 5 2.9171689899156377
Gene
Category Term PValue Genes FDR
Count
MOGAT2, PIK3C2G, CHKB, PI4KA, PNPLA2, IG PIGP,
GOTERM_ GO:0046486~glycerolipid
18 2,66E-05 CHPTl, G6PC, LRAT, INSIG2, CD81, FABP3, PCYTIA, PPAP2A, 0,046874419 BP_ALL metabolic process
FABP5, PIP4K2C, PTDSS2
GOTERM_ GO:0046470~phosphatidylch
6 7,82E-05 LRAT, CH B, FABP3, PCYTIA, CHPTl, FABP5 0,137984141 BP ALL oline metabolic process
GG ERIVL GO:0006656~phosphatidylch
5 9,60E-05 CHKB, FABP3, PCYTIA, CHPTl, FABP5 0,169416734 BP ALL oline biosynthetic process
GOTERM_ GO:0045017~glycerolipid MOGAT2, CHKB, CD81, FABP3, PCYTIA, PPAP2A, PIGQ,
11 l,30E-04 0,228580933 BP ALL biosynthetic process CHPTl, PIGP, FABP5, PTDSS2
GPD2, CLN3, PIK3C2G, CHKB, HEXB, PI4KA, PIGQ, LPCAT3,
GOTERM_ GO:0019637~organophosphat
20 l,46E-04 PIGP, CHPTl, LRAT, SMPDL3A, PLA2G12A, CD81, FABP3, 0,257989254 BP_ALL e metabolic process
PCYTIA, CLN8, FABP5, PIP4K2C, PTDSS2
CLN3, PIK3C2G, CHKB, HEXB, PI4KA, PIGQ, LPCAT3, PIGP,
GOTERM_ GO:0006644~phospholipid
19 l,63E-04 CHPTl, LRAT, SMPDL3A, PLA2G12A, CD81, FABP3, PCYTIA, 0,287446617 BP ALL metabolic process
CLN8, FABP5, PIP4K2C, PTDSS2
GOTERM_ GO:0006650~glycerophosphol PIK3C2G, CHKB, PI4KA, PIGQ, PIGP, CHPTl, LRAT, CD81,
13 2,89E-04 0,509294772 BP ALL ipid metabolic process FABP3, PCYTIA, PIP4K2C, FABP5, PTDSS2
CYB5R3, HSD17B11, MY05A, CHKB, HEXB, CD74, STARD5,
GOTERM_ GO:0008610~lipid INSIG2, PCYTIA, PPAP2A, GAL3ST1, PTDSS2, MOGAT2, UGCG,
26 3,97E-04 0,699001749 BP_ALL biosynthetic process FDPS, FADS2, ACACB, PIG LPCAT3, PIGP, CHPTl, ACSM3,
CD81, FABP3, RDH16, FABP5
GOTERM_ GO:0046474~glycerophosphol CHKB, CD81, FABP3, PCYTIA, PIGQ, CHPTl, PIGP, FABP5,
9 5,73E-04 1,006350545 BP ALL ipid biosynthetic process PTDSS2
GO:0042439~ethanolamine
GOTERM_
and derivative metabolic 6 6,86E-04 LRAT, CHKB, FABP3, PCYTIA, CHPTl, FABP5 1,20487095 BP_ALL
process
GOTERM_ GO:00086S4~phospholipid CHKB, CD81, HEXB, FABP3, PCYTIA, PIGQ, CHPTl, PIGP,
11 0,00237237 4,106602119 BP ALL biosynthetic process LPCAT3, FABP5, PTDSS2
FARS2, CHKB, HEX A, HEXB, P4HA2, CSAD, MTPN, ATG7,
GOTERM_ GO:0009308~amine CHST14, PCYTIA, PPAP2A, CLN3, DDC, MAOA, CHI3L1, GGH,
26 0,00393724 6,72777125 BP_ALL metabolic process CHPTl, GNS, ADI1, LYVE1, LRAT, FABP3, COMT1, FABP5,
CLN6, PRODH
GOTERM_ GO:0006576~biogenic amine DDC, LRAT, CHKB, MTPN, MAOA, FABP3, PCYTIA, CHPTl,
10 0,00609099 10,22495032 BP ALL metabolic process COMT1, FABP5
GO:0006575~cellular amino
GOTERM_ DDC, MAOA, CHKB, CHPTl, LRAT, P4HA2, CSAD, MTPN, GPX4,
acid derivative metabolic 14 0,00623139 10,44857697 BP_ALL GPX3, FABP3, PCYTIA, COMT1, FABP5
process
GO:0006519~cellular amino DDC, CLN3, FARS2, CHKB, MAOA, GGH, CHPTl, ADI1, LRAT,
GOTERM_
acid and derivative metabolic 20 0,04415718 P4HA2, CSAD, MTPN, GPX4, ATG7, GPX3, FABP3, PCYTIA, 54,94629325 BP ALL
process COMT1, FABP5, PRODH
GOTERM_ GO:0044106~cellular amine CLN3, DDC, FARS2, CHKB, MAOA, GGH, CHPTl, ADI1, LRAT,
17 0,07196099 73,2456915 BP ALL metabolic process CSAD, MTPN, ATG7, FABP3, PCYTIA, COMT1, FABP5, PRODH
GOTERM_ GO:0006520~cellular amino
7 0,81576403 ADI1, CLN3, CSAD, FARS2, ATG7, GGH, PRODH 100 BP ALL acid metabolic process
Annotation Enrichment Score:
Cluster 6 2.73576572S1015675
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006732~coenzyme CES3, NAMPT, AC02, CS, PDK4, ACOT2, ACOTl, IDH3B, DLAT,
16 9,59E-04 1,679097379 BP ALL metabolic process ACOT4, IDH3A, ACOT3, MTHFS, GPX4, GPX3, IDH2
GOTERM_ GO:0006084~acetyl-CoA
7 0,00157515 AC02, PDK4, CS, IDH2, IDH3B, DLAT, IDH3A 2,744699804 BP ALL metabolic process
GOTERM_ GO:00S1186~cofactor CES3, NAMPT, AC02, CS, PDK4, AC0T2, ACOTl, IDH3B, DLAT,
17 0,00410865 7,010728038 BP ALL metabolic process ACOT4, IDH3A, ACOT3, MTHFS, ALASl, GPX4, GPX3, IDH2
Annotation Enrichment Score:
Cluster 7 2.367231306000598
Gene
Category Term PValue Genes FDR
Count
PPARA, JUB, HPS4, PPARG, F2RL1, PRDX2, ELK3, TLR5, CCL5,
GOTERM_ GO:0009611~response to TIMP3, DTNBP1, MIF, CCL25, S LCI A 2, ANXA8, MTPN, CNR2,
33 2,42E-05 0,042795295 BP ALL wounding VNN1, CFD, ENTPD2, BMP2, LIPA, PTGER3, TGFBR2, F8,
ANXA5, IGHG, NUPR1, STAB1, BAX, CD81, CTSB, BMP6 JUB, PPARA, ENPP2, HPS4, PPARG, F2RL1, PRDX2, ELK3, KIT,
TLR5, CCL5, TIMP3, DTNBP1, MIF, CCL25, ANXA8, SLC1A2,
GOTERM_ GO:0009605~response to PDE6D, MTPN, ATG7, CNR2, TEK, CKLF, VNNl, CFD, ENTPD2,
46 4.49E-04 0,78953097 BP_ALL external stimulus CYR61, CLN3, BMP2, PTGER3, LIPA, ACADS, TGFBR2, F8,
ANXA5, GPR98, IGHG, G6PC, NUPRl, STABl, FYN, BAX, CD81,
ARSA, CTSB, BMP6
JUB, PPARA, ZMAT3, PPARG, HPS4, F2RL1, PRDX2, FOX03,
TLR5, PTTG1, APOA4, SLC1A2, INSIG2, HSF2, ATG7, GPX4,
GPX3, NSMCE2, VNNl, GPX7, CFD, CLN3, PTGER3, ACADS, F8,
TOPBP1, WFDC12, IGHG, DCLRE1A, CD81, HIPK2, DDB2,
GOTERM_ GO:0006950~response to
67 0,0099157 HSPB1, H2-AA, CTSB, CLN8, ELK3, CCL5, 0BFC2A, DTNBP1, 16,13247464 BP ALL stress
TIMP3, CD74, MIF, ADRB3, CCL25, ANXA8, RAD51L1, MTPN,
CNR2, IDH2, CLEC2H, DEFBl, ENTPD2, FGD4, TXNIP, BMP2,
LIPA, TGFBR2, COTL1, ANXA5, HERPUD2, FCGR2B, NUPRl,
STABl, BAX, APBB1, BMP6
JUB, F2RL1, PTTGl, TLR5, FOX03, WNT2, APOA4, INSIG2,
ATG7, VNNl, CFD, MY06, F8, TOPBP1, IRS1, WFDC12, IGHG,
DCLRE1A, LRAT, AAAS, ABCB1A, JUN, HSPB1, GBP1, PPP5C,
ME1, ENPP1, ENPP2, NTAN1, ACP5, ELK3, CCL5, OBFC2A,
TIMP3, ADA, CD74, TTC3, EPHB2, ADRB3, PDE6D, RAD51L1,
LOC641240, MTPN, CNR2, TEK, LOC677317, CKLF, IDH2,
PCYTIA, ENTPD2, DEFBl, FGD4, UNC119, IGH, BMP2, RMCS2,
KLF10, IGJ, TGFBR2, EPHX1, HERPUD2, RMCS5, H2-EB1,
GOTERM_ GO:0050896~response to
123 0,01638127 ASNA1, BMP6, PPARA, BCAR1, HEXA, ZMAT3, HEXB, HPS4, 25,29329126 BP ALL stimulus
PPARG, RHOQ, PRDX2, SLC1A2, HSF2, GPX4, GPX3, NSMCE2,
GPX7, CYR61, CLN3, DDC, PTGER3, ACADS, SLC24A6, LPIN1,
GPR98, G6PC, CAPN10, HIPK2, CD81, PKLR, DDB2, H2-AA,
LOC100047575, CTSB, CLN8, CLN6, MY05A, KIT, DTNBP1,
MIF, CCL25, ANXA8, SORBS1, CLEC2H, TES, TXNIP, CES3,
WDTC1, LIPA, H2-AB1, SNAI2, ANXA5, COTL1, CPT1A, APRT,
C920025E04RIK, FCGR2B, NUPRl, FYN, STABl, BAX, ARSA,
SLC18A1, APBB1
GOTERM_ GO:0006954~inflammatory BMP2, PTGER3, LIPA, PPARG, F8, PRDX2, TLR5, CCL5, MIF,
17 0,02729238 38,64750348 BP ALL response IGHG, CCL25, NUPRl, STABl, CNR2, VNNl, CFD, BMP6
PPARG, PRDX2, TLR5, CCL5, CD74, MIF, APOA4, CCL25, CNR2,
GOTERM_ GO:0006952~defense
25 0,12976023 VNNl, CFD, CLEC2H, DEFBl, BMP2, PTGER3, LIPA, F8, COTL1, 91,40298934 BP_ALL response
IGHG, WFDC12, NUPRl, FCGR2B, STABl, H2-AA, BMP6
Annotation Enrichment Score:
Cluster 8 1.8876140438548106
Gene
Category Term PValue Genes FDR
Count
RTN4, ENPP1, LM02, PPARG, GNA12, RHOQ, PRDX2, KIT,
FOX03, TTL, CD74, TTC3, ADA, EPHB2, MAPT, TEK, VNNl,
GOTERM_ GO:0050793~regulation of RHOC, MBNL3, ANGPT2, CDC42EP3, BMP2, AR, KLF10,
40 0,00165174 2,876328129 BP_ALL developmental process FOXA1, TGFBR2, GAS2, RBI, LPIN1, KITL, HHEX, NOTCH1,
CD36, STABl, FYN, BAX, H2-AA, ID4, LOC100047556, IGFBP3,
TOB2
RTN4, ENPP1, LM02, PPARG, PRDX2, FOX03, ADA, TTC3,
GOTERM_ GO:0045595~regulation of CD74, TTL, EPHB2, MAPT, VNNl, RHOC, MBNL3, BMP2, AR,
30 0,00172221 2,997277095 BP_ALL cell differentiation KLF10, FOXA1, TGFBR2, RBI, KITL, LPIN1, NOTCH1, CD36,
BAX, H2-AA, ID4, LOC100047556, IGFBP3, TOB2
GO:0045597~positive BMP2, KLF10, FOXA1, TGFBR2, PPARG, FOX03, RBI, KITL,
GOTERM_
regulation of cell 17 0,00278765 CD74, ADA, EPHB2, NOTCH 1, CD36, MAPT, H2-AA, VNNl, 4,808889573 BP_ALL
differentiation LOC100047556, IGFBP3
GO:00S1094~positive BMP2, KLF10, FOXA1, TGFBR2, PPARG, FOX03, RBI, KITL,
GOTER _
regulation of developmental 19 0,00388231 ADA, CD74, EPHB2, NOTCH1, CD36, BAX, MAPT, H2-AA, 6,636917567 BP_ALL
process VNNl, LOC100047556, IGFBP3, TOB2
GO:0051093~negative
G0TERM_ RTN4, ENPP1, LM02, TGFBR2, PRDX2, TTC3, CD74, EPHB2,
regulation of developmental 16 0,05272608 61,56870566 BP_ALL HHEX, NOTCH1, STABl, ID4, RHOC, MBNL3, ANGPT2, TOB2
process
RTN4, ENPP1, LM02, PPARG, PRDX2, FOX03, TTL, CD74,
TTC3, ADA, EPHB2, AP0A4, ADRB3, MAPT, TEK, VNNl, RHOC,
GO:0051239~regulation of
GOTER _ MBNL3, ANGPT2, SGPL1, BMP2, AR, MY06, SMAD7, KLF10,
multicellular organismal 40 0,13898671 92,87765641 BP_ALL FOXA1, TGFBR2, RBI, ANXA5, CSRP3, KITL, HHEX, ATXN2,
process
NOTCH 1, STABl, BAX, H2-AA, ID4, LOC100047556, IGFBP3,
TOB2
GOTERM_ GO:0002682~regulation of LM02, BCAR1, KLF10, TGFBR2, PRDX2, FOX03, RBI, KITL,
17 0,2712354 99,62500212 BP ALL immune system process ADA, CD74, IGHG, FCGR2B, CD81, H2-AA, VNNl, CFD, T0B2
Annotation Enrichment Score:
Cluster 9 1.7027182480945 Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006084~acetyl-CoA
7 0,00157515 AC02, PDK4, CS, IDH2, IDH3B, DLAT, IDH3A 2,744699804 BP ALL metabolic process
GOTERM_ GO:0006099~tricarboxylic
5 0,01426025 AC02, CS, IDH2, IDH3B, IDH3A 22,39759743 BP ALL acid cycle
GOTERM_ GO:0046356~acetyl-CoA
5 0,01655909 AC02, CS, IDH2, IDH3B, IDH3A 25,53136743 BP ALL catabolic process
GOTERM_ GO:0009060~aerobic
5 0,02478969 AC02, CS, IDH2, IDH3B, IDH3A 35,80011916 BP ALL respiration
GOTERM_ GO:0009109~coenzyme
5 0,03143028 AC02, CS, IDH2, IDH3B, IDH3A 43,09559406 BP ALL catabolic process
GOTERM_ GO:0045333~cellular
7 0,03617568 AC02, CS, IDH2, IDH3B, PPARGC1A, IDH3A, NDUFSl 47,82187491 BP ALL respiration
GOTERM_ GO:0051187~cofactor
5 0,04316976 AC02, CS, IDH2, IDH3B, IDH3A 54,11749686 BP_ALL catabolic process
GO:0015980~energy
GOTERM_ G6PC, AC02, CS, GYG, IDH2, IDH3B, PPARGC1A, IDH3A,
derivation by oxidation of 9 0,05278997 61,61443744 BP_ALL NDUFSl
organic compounds
Annotation Enrichment Score:
Cluster 10 1.6403509917262429
Gene
Category Term PValue Genes FDR
Count
GO:0022603~regulation of
GOTERM_ RTN4, AR, TGFBR2, GNA12, RHOQ, GAS2, TTC3, TTL, EPHB2,
anatomical structure 17 0,00533618 9,013630934 BP_ALL HHEX, STAB1, FYN, BAX, MAPT, TEK, CDC42EP3, ANGPT2
morphogenesis
GOTERM_ GO:0022604~regulation of RTN4, FYN, MAPT, GNA12, RHOQ, GAS2, CDC42EP3, TTC3,
10 0,02018437 30,23188025 BP_ALL cell morphogenesis TTL, EPHB2
GO:0051129~negative
GOTERM_ RTN4, LIMAl, MAD2L1, MAPT, MTAP4, RHOQ, STMNl, TTC3,
regulation of cellular 9 0,04080161 52,07079718 BP_ALL EPHB2
component organization
GO:0051128~regulation of RTN4, LIMAl, GNA12, MTAP4, RHOQ, GAS2, MFGE8, TTL,
GOTERM_
cellular component 21 0,06247028 TTC3, EPHB2, WNT2, IGHG, MAD2L1, FCGR2B, SORBS1, FYN, 67,98111203 BP_ALL
organization MAPT, CENPV, STMNl, CDC42EP3, TES
Annotation Enrichment Score:
Cluster 11 1.6328109975956944
Gene
Category Term PValue Genes FDR
Count
GOTERM_
GO:0042552~myelination 7 0,00402239 MY05A, CD9, TSC1, FYN, HEXA, HEXB, GAL3ST1 6,868436545 BP ALL
GOTERM_ GO:0008366~axon
7 0,00526083 MY05A, CD9, TSC1, FYN, HEXA, HEXB, GAL3ST1 8,891880517 BP_ALL ensheathment
GOTERM_ GO:0007272~ensheathment
7 0,00526083 MY05A, CD9, TSC1, FYN, HEXA, HEXB, GAL3ST1 8,891880517 BP_ALL of neurons
GOTER _ GO:0001508~regulation of
8 0,00696495 MY05A, CLN3, CD9, TSC1, FYN, HEXA, HEXB, GAL3ST1 11,6084459 BP ALL action potential
GOTERM_ GO:0019228~regulation of
7 0,01063869 MY05A, CD9, TSC1, FYN, HEXA, HEXB, GAL3ST1 17,20714653 BP ALL action potential in neuron
MY05A, GABRD, CLN3, MY06, SLC25A4, HEXA, MAOA, HEXB,
GOTER _ GO:0019226~transmission of
18 0,01424866 WNT2, P2RX4, CD9, H MT, TSC1, FYN, COMTl, CLN8, 22,38148337 BP_ALL nerve impulse
GAL3ST1, TES
MY05A, FTL1, FTL2, HEXA, HEXB, L0C434624, ACP5, PRDX2,
ATP6V0C-PS2, F0X03, ATP6V0C, ADRB3, CD9, TPPl, SLC4A4,
GAL3ST1, NDUFSl, GLRX, CLN3, WDTC1, LIPA, PTGER3,
GOTERM_ GO:0042592~homeostatic
36 0,02085082 SMAD7, FOXA1, BPGM, RBI, CSRP3, KDR, HBA-A1, HBA-A2, 31,0649521 BP_ALL process
P2RX4, G6PC, CCNB2, TSC1, LARGE, FYN, BAX,
LOC100047575, LOC100047556, ASNA1, 2700094K13RIK,
CLN6
GOTERM_ GO:0042391~regulation of MY05A, CLN3, CD9, P2RX4, TSC1, SMAD7, FYN, HEXA, HEXB,
11 0,02751891 38,89926776 BP ALL membrane potential GAL3ST1, NDUFSl
MY05A, FTL1, FTL2, HEXA, LOC434624, HEXB, PRDX2,
GOTER _ GO:0019725~cellular ATP6V0C-PS2, ATP6V0C, CD9, GAL3ST1, NDUFSl, GLRX, CLN3,
23 0,03127876 42,9382216 BP_ALL homeostasis WDTC1, PTGER3, SMAD7, CSRP3, P RX4, LARGE, TSC1, FYN,
BAX, LOC100047575, ASNA1, 2700094K13RIK, CLN6
MY05A, CLN3, WDTC1, PTGER3, FTL1, FTL2, SMAD7, HEXA,
GOTER _ GO:0055082~cellular HEXB, LOC434624, ATP6V0C-PS2, CSRP3, ATP6V0C, P2RX4,
19 0,03268371 44,38176589 BP_ALL chemical homeostasis CD9, TSC1, FYN, BAX, LOC100047575, ASNA1, NDUFSl,
GAL3ST1, CLN6
Figure imgf000033_0001
LDH B, RPL13, ADCY6, PPP2R5C, BBX, PGAMl, MPV17, MYLI P,
PRKG2, PTTG1, OGDH, DNASE1L3, DNASE1L1, INSIG2,
CYP7A1, NT5C2, VNN1, RARB, PDHA1, CFD, SG PL1, RREB1,
HKDC1, UGCG, F8, ZFP467, PPARGC1A, LPCAT3, PPARGC1B,
IGHG, EBPL, DCLRE1A, NNT, CD36, PIAS3, JUN, BACE1,
CAMK1, LOC100047005, PRODH, HSD17B11, ENPP5, ERMP1,
ENPP1, ENPP2, FARS2, CHKB, MME, ACP5, ATP6V0C-PS2,
ASB13, OBFC2A, NAGK, ACAT1, ADA, CD74, ATP6V0B,
HADHB, EPHB2, ATP6V0C, TCF21, IDH2, AI464131, GPD2,
OSBPL5, DNMT3A, PTGR2, UFSP1, CYP46A1, SMAD7, KLF10,
MAOA, TGFBR2, TAOK3, GGH, CHI3L1, PPFIBP2, LOC280487,
TKT, ACACB, LOC100044230, UAP1L1, DLAT, PRPSAP1, CRYZ,
KDR, CYP4B1, EPHA7, NOTCH 1, PAPPA2, CYP8B1, CML5,
COMT1, ACAD10, CML3, RE RE, H LF, PPARA, CYP2J9, PPARG,
CYP2J6, ZEB2, CDT1, CCNE2, USP18, P4HA2, HSF2, SMPDL3A,
GPX4, BAG2, GPX3, CHST14, NSMCE2, GPX7, DPP7, DEDD2,
DPP4, CLN3, AR, PIK3C2G, AC02, PI4KA, MMP15, DECR1,
ST6GALNAC2, MMP12, G6PC, OSBPL11, CLN8, PMPCB, CLN6,
MY05A, ATG10, ECH 1, FUT8, RAB3D, LOC640611, USP2,
ABHD4, KIT, SEC14L2, PLCL2, PET112L, GALK1, GNPTAB,
FMOl, PLA2G12A, FM02, PITRM1, GATAD2A, ACAA1A,
ACAA1B, CAR2, CAR3, TES, PDK1, CES3, PDK2, MOGAT2,
CPT1B, PDK4, CS, FADS2, SNAI2, LOC100044896, CPT1A,
APRT, ACSM3, DUSP3, PTP4A3, ADCY9, RPS6KA1, LARGE,
GOTERM. GO:0008152~metabolic FYN, GYG, ARSA, NLN, AACS, APBB1, HPGD, LRP4, MKRN1,
348 4.80E-06 0,008470582 BP ALL process GRPEL2, GNPDA1, CNDP2, DBF4, TCEAL8, LOC100045031,
TCEAL1, TTL, AP0A4, WNT2, ASPA, STARD5, ST3GAL3,
SMARCD3, ATG7, OLIG1, ZFP503, ATOH8, FBX021, HADH,
NQ02, PABPN1, PDXK, ENC1, TOPBP1, PNPLA2, H DAC11,
CYP2B10, CHPT1, WEE1, GNS, H HEX, SCCPDH, RENBP, LRAT,
GTF2IRD1, NEU1, PPP5C, ME1, LOC100048346, EIF4E3,
RAG1AP1, CTSA, ST8SIA3, ATP6V1B2, ELK3, CYP4A12A, SBK1,
CSAD, RAD51L1, MTPN, PTPLA, TEK, LOC677317, PCYT1A,
ENTPD2, GAL3ST1, FGD4, BHLHE22, FOXA1, FDPS, EPHX1,
IDH3B, AK2, BPGM, CRAT, WIPI1, IDH3A, 2410022L05RIK,
P2RX4, LYVE1, PLK2, ST8SIA4, NDUFV1, FABP3, FBX032,
CYP2C38, UBE2E2, FABP5, PIP4K2C, CYB5R3, NAMPT, SOLH,
CYP2S1, H EXA, HEXB, E2F8, ACOT2, ACOT1, PRDX2, HLCS,
ACSF3, ACOT4, ACOT3, CASP6, ALASl, TPPl, SRD5A3, SOX17,
PAK1, NDUFS1, RTN4IP1, PTDSS2, FAM176A, DDC, SSBP3,
CTSZ, SGK3, ACADS, CYCS, RBI, CDK4, PIGQ, ACADL, PIGP,
LPIN1, DHRS7, DNASE2B, ATP6V1A, CAPN10, CYP4A31, PKLR,
HIPK2, CD81, DDB2, UCHL5, UBD, LOC100047575, CTSB,
UGP2, XYLB, PRKCZ, FRK, EGLN3, UPP2, TRIB3, EGLN 1, DCI,
ALDH3A2, PBLD, PRSS8, DDH D2, AKR1A4, THFS, OXCT1,
CAMK2D, TOR1B, UCK1, PTS, PPAP2A, BDH1, GLRX, PTPRB,
TXNIP, GSTA2, WDTCl, LIPA, PSAP, FUCA2, GDPDl, CYP4A10,
AKR1B8, ADI1, SULF2, HSDL2, AKR1B3, BAX, SUMF1, CENPV,
LIPG, SETD8, LOC100047556, RDH16, CYP4A14, NFIC, IGFBP3,
RETSAT
LDHB, RPL13, ADCY6, PPP2R5C, PGA 1, BBX, MPV17, MY LIP,
PRKG2, PTTGl, OGDH, DNASE1L3, DNASEILI, INSIG2, NT5C2,
RARB, PDHA1, SGPL1, RREB1, HKDC1, UGCG, ZFP467,
PPARGC1A, LPCAT3, PPARGC1B, DCLRE1A, CD36, PIAS3, JUN,
BACE1, CAMK1, LOC100047005, PRODH, ENPP5, FARS2,
CHKB, ACP5, ATP6V0C-PS2, ASB13, OBFC2A, NAGK, ADA,
CD74, ATP6V0B, HADHB, EPHB2, ATP6V0C, TCF21, IDH2,
GPD2, DNMT3A, UFSP1, SMAD7, KLF10, MAOA, TGFBR2,
TAOK3, GGH, PPFIBP2, LOC280487, ACACB, DLAT, PRPSAP1,
KDR, EPHA7, NOTCH1, COMT1, RERE, HLF, PPARA, PPARG,
ZEB2, CDT1, CCNE2, USP18, P4HA2, HSF2, SMPDL3A, GPX4,
GPX3, CHST14, NSMCE2, DEDD2, CLN3, AR, PIK3C2G, AC02,
PI4KA, ST6GALNAC2, G6PC, CLN8, CLN6, MY05A, ATG10,
ECH1, FUT8, RAB3D, USP2, LOC640611, KIT, SEC14L2,
PET112L, GALK1, GNPTAB, PLA2G12A, FM02, GATAD2A,
ACAA1A, ACAA1B, CAR2, CAR3, TES, PDK1, CES3, PDK2,
MOGAT2, CPT1B, CS, PDK4, FADS2, SNAI2, CPT1A, APRT,
ACSM3, DUSP3, RPS6KA1, LARGE, ADCY9, PTP4A3, FYN, GYG,
I GOTERM_ I GO:0044237~cellular ARSA, AACS, APBB1, HPGD, LRP4, MKRN1, GRPEL2, GNPDA1,
267 0,04156796 52,74236683 BP_ALL I metabolic process DBF4, TCEAL8, LOC100045031, TCEAL1, TTL, APOA4, WNT2,
ASPA, ST3GAL3, SMARCD3, ATG7, 0L|G1, ATQH8, ZFP503,
FBX021, HADH, PABPN1, PDXK, ENC1, T0PBP1, PNPLA2,
HDAC11, CHPT1, WEE1, HHEX, RENBP, LRAT, GTF2IRD1,
PPP5C, LOC100048346, ME1, EIF4E3, RAG1AP1, ST8SIA3,
ELK3, ATP6V1B2, CYP4A12A, SBK1, CSAD, RAD51L1, MTPN,
PTPLA, LOC677317, TEK, PCYT1A, ENTPD2, GAL3ST1, FGD4,
BHLHE22, FOXA1, FDPS, IDH3B, AK2, EPHX1, BPGM, CRAT,
WIPI1, ΙΌΗ3Α, 241OO22L05RIK, P2RX4, PLK2, ST8SIA4,
NDUFV1, FABP3, FBX032, UBE2E2, FABP5, PIP4K2C, NAMPT,
HEXA, HEXB, E2F8, ACOT2, ACOT1, HLCS, PRDX2, ACSF3,
ACOT4, ACOT3, ALASl, TPPl, SOX17, PAKl, NDUFSl, PTDSS2,
FAM176A, DDC, SSBP3, SGK3, ACADS, CYCS, RBI, PIGQ,
ACADL, CDK4, PIGP, DNASE2B, ATP6V1A, CYP4A31, PKLR,
HIPK2, CD81, DDB2, UCHL5, UBD, LOC100047575, XYLB, FRK,
PRKCZ, TRIB3, UPP2, DCI, ALDH3A2, AKR1A4, MTHFS, OXCT1,
TORIB, CAMK2D, PTS, PPAP2A, GLRX, TXNIP, PTPRB, WDTCl,
PSAP, FUCA2, GDPD1, CYP4A10, ADI1, SULF2, BAX, SETD8,
LOC100047556, NFIC, RDH16, IGFBP3, RETSAT
LDHB, RPL13, ADCY6, PPP2R5C, PGAM1, BBX, PV17, MY LIP,
PRKG2, PTTG1, OGDH, DNASE1L3, DNASEILI, INSIG2,
CYP7A1, NT5C2, RARB, PDHA1, CFD, SGPL1, RREB1, H KDC1,
UGCG, ZFP467, PPARGC1A, LPCAT3, PPARGC1B, IGHG, EBPL,
DCLRE1A, PIAS3, JUN, BACE1, CAMK1, LOC100047005,
PRODH, HSD17B11, ENPP5, ERMP1, ENPP2, FARS2, CH KB,
MME, ATP6V0C-PS2, ASB13, OBFC2A, NAGK, ADA, CD74,
ATP6V0B, HADHB, EPH B2, ATP6V0C, TCF21, IDH2, AI464131,
GPD2, DNMT3A, OSBPL5, UFSP1, CYP46A1, SMAD7, KLF10,
AOA, TGFBR2, TAOK3, GGH, CHI3L1, PPFIBP2, LOC280487,
ACACB, LOC100044230, DLAT, PRPSAP1, KDR, EPHA7,
NOTCH1, PAPPA2, COMT1, RERE, HLF, PPARA, PPARG, ZEB2,
CDT1, CCNE2, USP18, P4HA2, HSF2, S PDL3A, GPX4, BAG 2,
GPX3, CHST14, NSMCE2, DPP7, DEDD2, DPP4, CLN3, AR,
PIK3C2G, PI4KA, MMP15, ST6GALNAC2, MMP12, G6PC,
OSBPL11, CLN8, PMPCB, CLN6, MY05A, ATG10, ECH 1, FUT8,
RAB3D, USP2, LOC640611, ABH D4, KIT, SEC14L2, PET112L,
PLCL2, GALK1, GNPTAB, PLA2G12A, PITRM1, GATAD2A,
ACAA1A, ACAA1B, TES, PDK1, PDK2, MOGAT2, CPT1B, CS,
GOTERM_ GO:0044238~primary PDK4, FADS2, SNAI2, CPTIA, APRT, ACS 3, DUSP3, RPS6KA1,
278 0,08073206 77,37523782 BP_ALL metabolic process ADCY9, PTP4A3, FYN, GYG, NLN, AACS, APBBl, HPGD,
MKRN1, GRPEL2, GNPDA1, CNDP2, DBF4, TCEAL8,
LOC100045031, TCEALl, TTL, WNT2, STARD5, ST3GAL3,
SMARCD3, ATG7, OLIG1, ATOH8, ZFP503, FBX021, HADH,
PABPN 1, ENC1, TOPBP1, PNPLA2, HDAC11, CHPT1, WEE1,
GNS, HHEX, RENBP, LRAT, GTF2IRD1, PPP5C, LOC100048346,
EIF4E3, RAG1AP1, CTSA, ST8SIA3, ELK3, ATP6V1B2,
CYP4A12A, SBK1, CSAD, RAD51L1, TPN, TEK, PCYT1A,
ENTPD2, GAL3ST1, FGD4, BHLHE22, FOXA1, FDPS, AK2,
BPGM, CRAT, 2410022L05RIK, LYVE1, PLK2, ST8SIA4, FABP3,
FBX032, UBE2E2, FABP5, PIP4K2C, CYB5R3, NAMPT, SOLH,
HEXA, HEXB, E2F8, ACOT2, ACOT1, HLCS, PRDX2, ACSF3,
ACOT4, ACOT3, CASP6, TPPl, SRD5A3, SOX17, PAKl, NDUFSl,
PTDSS2, DDC, SSBP3, CTSZ, SGK3, ACADS, RBI, PIGQ, ACADL,
CDK4, PIGP, LPIN1, DNASE2B, ATP6V1A, CAPN10, CYP4A31,
PKLR, HIPK2, CD81, DDB2, UCHL5, UBD, LOC100047575,
CTSB, XYLB, PRKCZ, FRK, TRIB3, UPP2, DCI, PRSS8, DDHD2,
AKR1A4, TORiB, CA K2D, PPAP2A, TXNIP, PTPRB, WDTC1,
LIPA, PSAP, FUCA2, GDPD1, CYP4A10, ADI1, BAX, LIPG,
SETD8, LOC100047556, NFIC, RDH 16, IGFBP3, RETSAT
MKRN1, GRPEL2, RPL13, CNDP2, DBF4, PPP2R5C, BBX,
MPV17, TCEAL8, MYLIP, PRKG2, LOC100045031, PTTGl,
DNASE1L3, TCEALl, TTL, DNASEILI, WNT2, APOA4, ST3GAL3,
SMARCD3, ATG7, OLIG1, ZFP503, RARB, ATOH8, FBX021,
CFD, PABPN1, RREB1, ENC1, ZFP467, TOPBP1, HDAC11,
PPARGC1A, PPARGC1B, WEE1, GNS, HH EX, IGHG, DCLRE1A,
CD36, PIAS3, GTF2IRD1, JUN, BACE1, CAMK1, PPP5C,
LOC100048346, ER P1, EIF4E3, RAG1AP1, FARS2, MME,
ST8SIA3, CTSA, ASB13, ELK3, OBFC2A, CD74, EPHB2, TCF21,
SBK1, RADS1L1, TEK, FGD4, DNMT3A, UFSP1, BHLHE22,
SMAD7, KLF10, FOXA1, TGFBR2, TAOK3, CHI3L1, PPFIBP2,
GOTERM_ GO:0043170~macromolecule LOC280487, KDR, 2410022L05RIK, EPHA7, NOTCH1, LYVE1,
172 0,9999388 100 BP_ALL metabolic process PLK2, ST8SIA4, PAPPA2, FBX032, UBE2E2, RERE, PPARA, H LF,
SOLH, HEXA, HEXB, PPARG, E2F8, H LCS, PRDX2, ZEB2, CDT1,
CCNE2, CASP6, USP18, P4HA2, HSF2, TPPl, GPX4, BAG2,
CHST14, NSMCE2, PAKl, SOX17, DPP7, DPP4, DEDD2, CLN3,
CTSZ, AR, SSBP3, SGK3, RBI, MMP15, CDK4, PIGQ, PIGP,
MMP12, ST6GALNAC2, DNASE2B, G6PC, CAPN10, CYP4A31,
CD81, HIPK2, DDB2, UCHL5, UBD, CTSB, CLN8, PMPCB, CLN6,
FRK, PRKCZ, ATG10, RAB3 D, FUT8, USP2, LOC640611, TRIB3,
KIT, SEC14L2, PET112L, PRSS8, PITRM1, TORIB, CAMK2D,
GATAD2A, PPAP2A, TES, PDK1, PTPRB, TXNIP, PDK2, PDK4,
SNAI2, CYP4A10, DUSP3, PTP4A3, LARGE, RPS6KA1, FYN,
GYG, NLN, SETD8, LOC100047556, NFIC, IG FBP3, APBBl, LRP4 KRN1, GRPEL2, RPL13, DBF4, PPP2R5C, BBX, PV17,
TCEAL8, MYLIP, PRKG2, PTTG1, LOC100045031, DNASE1L3,
TCEALl, TTL, DNASEILI, WNT2, APOA4, ST3GAL3, SMARCD3,
ATG7, OLIG1, ZFP503, RARB, ATOH8, FBX021, PABPN1,
RREB1, ENC1, ZFP467, TOPBP1, HDAC11, PPARGC1A,
PPARGC1B, WEE1, HHEX, DCLRE1A, CD36, PIAS3, GTF2IRD1,
JUN, BACE1, CAMK1, PPP5C, LOC100048346, EIF4E3,
RAG1AP1, FARS2, ST8SIA3, ASB13, ELK3, OBFC2A, CD74,
EPHB2, TCF21, SBK1, RAD51L1, TEK, FGD4, DNMT3A,
GO:0044260~cellular BHLHE22, UFSP1, SMAD7, KLF10, FOXA1, TGFBR2, TAOK3,
GOTERM_
macromolecule metabolic 146 0,99998727 PPFIBP2, LOC280487, KDR, 2410022L05RIK, EPHA7, NOTCH1, 100 BP_ALL
process PLK2, ST8SIA4, FBX032, UBE2E2, RERE, HLF, PPARA, HEXB,
PPARG, E2F8, HLCS, PRDX2, ZEB2, CDT1, CCNE2, USP18,
P4HA2, HSF2, GPX4, CHST14, NS CE2, PAKl, SOX17, DEDD2,
CLN3, AR, SSBP3, SGK3, RBI, CDK4, PIGa PIGP, ST6GALNAC2,
DNASE2B, G6PC, CYP4A31, HIPK2, CD81, UCHL5, DDB2, UBD,
CLN8, CLN6, FRK, PRKCZ, ATG10, RAB3D, FUT8, USP2,
LOC640611, TRIB3, KIT, SEC14L2, PET112L, TOR1B, CA K2D,
GATAD2A, PPAP2A, TES, PDK1, PTPRB, TXNIP, PDK2, PDK4,
SNAI2, CYP4A10, DUSP3, PTP4A3, LARGE, RPS6KA1, FYN,
GYG, SETD8, LOC100047556, NFIC, IGFBP3, APBB1, LRP4
Annotation Enrichment Score:
Cluster 15 1.4965140887139086
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006022~aminoglycan
7 0,02082964 GNS, LYVE1, HEXA, HEXB, CHST14, CHI3L1, CLN6 31,03861877 BP_ALL metabolic process
GOTERM_ GO:0030203~glycosaminoglyc
6 0,02477965 GNS, LYVE1, HEXA, HEXB, CHST14, CLN6 35,78845286 BP ALL an metabolic process
GOTERM_ GO:0005976~polysaccharide
9 0,03864324 GNS, LYVE1, G6PC, HEXA, HEXB, GYG, CHST14, CHI3L1, CLN6 50,13065424 BP_ALL metabolic process
GOTER _ GO:0001573~ganglioside
3 0,0517718 HEXA, HEXB, CLN6 60,87942986 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 16 1.420778818108307
Gene
Category Term PValue Genes FDR
Count
GOTERM_ JUB, PPARA, F2RL1, TGFBR2, HPS4, F8, ELK3, ANXA5, DTNBPl,
GO:0042060~wound healing 13 0,00250948 4,339015775 BP ALL TI P3, ANXA8, MTPN, ENTPD2
GOTERM_
GO:0050817~coagulation 7 0,07219589 ANXA8, HPS4, F2RL1, F8, ANXA5, ENTPD2, DTNBPl 73,36499201 BP ALL
GOTERM_ GO:0007596~blood
7 0,07219589 ANXA8, HPS4, F2RL1, F8, ANXA5, ENTPD2, DTNBPl 73,36499201 BP ALL coagulation
GOTERM_
GO:0007599~hemostasis 7 0,07622053 ANXA8, HPS4, F2RL1, F8, ANXA5, ENTPD2, DTNBPl 75,3327296 BP ALL
GOTERM_ GO:0050878~regulation of
8 0,07896324 ANXA8, PTGER3, HPS4, F2RL1, F8, ANXA5, ENTPD2, DTNBPl 76,59422912 BP_ALL body fluid levels
Annotation Enrichment Score:
Cluster 17 1.298410421523164
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0019216~regulation of PPARA, WDTC1, SORBS1, INSIG2, CD81, LOC100047575,
9 0,00271173 4,680867492 BP ALL lipid metabolic process PNPLA2, RBI, SEC14L2, IRS1
GOTERM_ GO:0019217~regulation of
3 0,18771501 PPARA, WDTC1, INSIG2, LOC100047575 97,45354778 BP ALL fatty acid metabolic process
GO:0010565~regulation of
GOTERM_
cellular ketone metabolic 3 0,25004789 PPARA, WDTC1, INSIG2, LOC100047575 99,37803917 BP ALL
process
Annotation Enrichment Score:
Cluster 18 1.2797840695666711
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0018106~peptidyl-
3 0,01606885 PDK1, PDK2, PDK4 24,87325716 BP ALL histidine phosphorylation
GOTERM_ GO:0018202~peptidyl-
3 0,03191667 PDK1, PDK2, PDK4 43,59797946 BP ALL histidine modification
GOTERM_ GO:0018193~peptidyl-amino
8 0,28225751 PDK1, PDK2, P4HA2, RAB3D, FYN, PDK4, KIT, EPHB2 99,71346369 BP ALL acid modification Annotation Enrichment Score:
Cluster 19 1.2341678490217864
Gene
Category Term PValue Genes FDR
Count
GO:0010828~positive
GOTERM_
regulation of glucose 3 0,03191667 SLC1A2, CAPNIO, SORBSl 43,59797946 BP_ALL
transport
GOTERM_ GO:0046326~positive
3 0,03191667 SLC1A2, CAPNIO, SORBSl 43,59797946 BP ALL regulation of glucose import
GOTERM_ GO:0046324~regulation of
4 0,04288639 SLC1A2, CAPNIO, SORBSl, RHOQ 53,87700764 BP ALL glucose import
GOTERM_ GO:0010827~regulation of
4 0,04893451 SLC1A2, CAPNIO, SORBSl, RHOQ 58,76053481 BP ALL glucose transport
GOTERM_ GO:0051050~positive
8 0,3156392 IGHG, SLC1A2, CAPNIO, SORBSl, FCGR2B, BAX, MFGE8, TRIP6 99,87639971 BP ALL regulation of transport
Annotation Enrichment Score:
Cluster 20 1.2125486305277777
Gene
Category Term PValue Genes FDR
Count
GO:0007179~transforming
GOTERM_
growth factor beta receptor 7 0,01443266 BMP2, FUT8, SMAD7, HIPK2, TGFBR2, ENG, HPGD 22,63686728 BP_ALL
signaling pathway
GO:0007178~transmembrane
GOTERM_ receptor protein
8 0,04441788 BMP2, FUT8, SMAD7, HIPK2, TGFBR2, ENG, HPGD, BMP6 55,16273837 BP_ALL serine/threonine kinase
signaling pathway
GO:0017015~regulation of
GOTERM_ transforming growth factor
3 0,35929408 SMAD7, HIPK2, ENG 99,9613961 BP_ALL beta receptor signaling
pathway
Annotation Enrichment Score:
Cluster 21 1.155711576390539
Gene
Category Term PValue Genes FDR
Count
GO:0002504~antigen
GOTERM_ processing and presentation RMCS2, FCGR2B, LOC641240, H2-EB1, H2-AA, H2-AB1, CD74,
6 9,OOE-04 1,576564873 BP_ALL of peptide or polysaccharide RMCS5
antigen via MHC class II
GO:0019886~antigen
GOTERM_ processing and presentation
5 0,00369456 RMCS2, FCGR2B, LOC641240, H2-EB1, H2-AA, H2-AB1, CD74 6,325760925 BP ALL of exogenous peptide antigen
via MHC class II
GO:0002495~antigen
GOTER _ processing and presentation
5 0,00369456 RMCS2, FCGR2B, LOC641240, H2-EB1, H2-AA, H2-AB1, CD74 6,325760925 BP_ALL of peptide antigen via MHC
class II
GO:0002478~antigen
GOTERM_
processing and presentation 5 0,01426025 RMCS2, FCGR2B, LOC641240, H2-EB1, H2-AA, H2-AB1, CD74 22,39759743 BP_ALL
of exogenous peptide antigen
GO:0019884~antigen
GOTERM_
processing and presentation 5 0,02799251 RMCS2, FCGR2B, LOC641240, H2-EB1, H2-AA, H2-AB1, CD74 39,42247792 BP_ALL
of exogenous antigen
GO:0048002~antigen
GOTER _
processing and presentation 5 0,05705308 RMCS2, FCGR2B, LOC641240, H2-EB1, H2-AA, H2-AB1, CD74 64,55281463 BP ALL
of peptide antigen
GOTERM_ GO:0019882~antigen RMCS2, C920025E04RIK, FCGR2B, LOC641240, H2-EB1, H2-
7 0,15678622 95,07442135 BP_ALL processing and presentation AA, H2-AB1, CD74, RMCS5
GOTERM_ GO:0016064~immunoglobulin
5 0,26995149 IGHG, IGH, FCGR2B, H2-AA, CD74 99,61316573 BP ALL mediated immune response
GOTERM_ GO:0019724~B cell mediated
5 0,28877094 IGHG, IGH, FCGR2B, H2-AA, CD74 99,75606052 BP ALL immunity
GOTERM_ G0:0002449~lymphocyte
5 0,39400118 IGHG, IGH, FCGR2B, H2-AA, CD74 99,98555827 BP ALL mediated immunity
GOTERM_ GO:0002252~immune
7 0,43292559 IGHG, IGH, FCGR2B, H2-AA, PRDX2, CFD, CD74 99,99552693 BP ALL effector process
GOTERM_ GO:0002250~adaptive
5 0,46927709 IGHG, IGH, FCGR2B, H2-AA, CD74 99,99861119 BP ALL immune response GO:0002460~adaptive
immune response based on
G0TERM_ somatic recombination of
5 0,46927709 IGHG, IGH, FCGR2B, H2-AA, CD74 99,99861119 BP_ALL immune receptors built from
immunoglobulin superfamily
domains
GOTERM_ GO:0002443~leukocyte
5 0,51456804 IGHG, IGH, FCGR2B, H2-AA, CD74 99,99971245 BP ALL mediated immunity
Annotation Enrichment Score:
Cluster 22 1.1504823364816825
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0035234~germ cell
3 0,01606885 BAX, KIT, KITL 24,87325716 BP ALL programmed cell death
GOTERM_ GO:0010623~developmental
3 0,03191667 BAX, KIT, KITL 43,59797946 BP ALL programmed cell death
GOTERM_ GO:0008354~germ cell
3 0,07487328 BAX, KIT, KITL 74,68982996 BP ALL migration
GO:0048070~regulation of
GOTERM_
pigmentation during 3 0,07487328 BAX, KIT, KITL 74,68982996 BP_ALL
development
GOTERM_ GO:0007281~germ cell
5 0,615081 REC8, BAX, FOX03, KIT, KITL 99,99999522 BP ALL development
Annotation Enrichment Score:
Cluster 23 1.148684887746027
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051329~interphase of
6 0,05305187 DBF4, CAMK2D, TPD52L1, ID4, RBI, CABLES1 61,80138503 BP ALL mitotic cell cycle
GOTERM_
GO:0051325~interphase 6 0,06113281 DBF4, CAMK2D, TPD52L1, ID4, RBI, CABLES1 67,1650356 BP ALL
GOTERM_ GO:0000082~G1/S transition
4 0,1104003 CAMK2D, ID4, RBI, CABLES1 87,32202667 BP ALL of mitotic cell cycle
Annotation Enrichment Score:
Cluster 24 1.1330790528423278
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0015711~organic anion
6 0,02242909 SLC1A2, PTGER3, SLC16A7, SLC25A4, SLC4A4, CLN8 33,00053884 BP ALL transport
GOTERM_ GO:0046942~carboxylic acid CLN3, CPTIB, SLC1A2, SLC25A4, SLC6A8, SLC6A6, PPARG,
10 0,02273674 33,37181501 BP ALL transport ABCC3, CTNS, CLN8
GOTERM_ GO:0015849~organic acid CLN3, CPTIB, SLC1A2, SLC25A4, SLC6A8, SLC6A6, PPARG,
10 0,02409596 34,9890414 BP ALL transport ABCC3, CTNS, CLN8
GOTERM_ GQ:0Q15718~monocarboxy!ic
4 0,04288639 CPTIB, SLC6A6, PPARG, ABCC3 53,87700764 BP ALL acid transport
GOTERM_ GO:0006865~amino acid
7 0,07622053 CLN3, SLC1A2, SLC25A4, SLC6A8, SLC6A6, CTNS, CLN8 75,3327296 BP ALL transport
GOTERM_ GO:0015813~L-glutamate
3 0,08743055 SLC1A2, SLC25A4, CLN8 80,11573649 BP ALL transport
GOTERM_ GO:0015800~acidic amino
3 0,08743055 SLC1A2, SLC25A4, CLN8 80,11573649 BP ALL acid transport
GOTERM_
GO:0015837~amine transport 7 0,18752111 CLN3, SLC1A2, SLC25A4, SLC6A8, SLC6A6, CTNS, CLN8 97,44279472 BP ALL
GOTERM_ GO:0015807~L-amino acid
3 0,18771501 SLC25A4, CTNS, CLN8 97,45354778 BP ALL transport
GOTERM_ GO:0006836~neurotransmitte
5 0,43197475 SLC25A4, SLC6A8, SLC6A6, SLC18A1, CLN8 99,99539265 BP ALL r transport
Annotation Enrichment Score:
Cluster 25 1.1254516800132688
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006576~biogenic amine DDC, LRAT, CHKB, MTPN, MAOA, FABP3, PCYTIA, CHPTl,
10 0,00609099 10,22495032 BP ALL metabolic process COMTl, FABP5
GO:0006725~cellular
GOTERM_
aromatic compound 9 0,10512693 MTHFS, DDC, MTPN, MAOA, EPHXl, PTS, COMTl, ADA, APRT 85,92767036 BP ALL
metabolic process
GOTERM_ GO:0009712~catechol
4 0,12889081 DDC, MTPN, MAOA, COMTl 91,25008637 BP ALL metabolic process GOTERM_ GO:0018958~phenol
4 0,12889081 DDC, MTPN, MAOA, COMT1 91,25008637 BP ALL metabolic process
GOTER _ GO:0034311~diol metabolic
4 0,12889081 DDC, MTPN, MAOA, COMT1 91,25008637 BP ALL process
GOTERM_ GO:0006584~catecholamine
4 0,12889081 DDC, MTPN, MAOA, COMT1 91,25008637 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 26 1.1161968378073097
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0007090~regulation of S
4 0,00935225 DBF4, GAS1, APBB1, CDT1 15,28584837 BP ALL phase of mitotic cell cycle
GOTER _ GO:0033261~regulation of S
4 0,01208691 DBF4, GAS1, APBB1, CDT1 19,32084991 BP ALL phase
GOTER _ GO:0045786~negative
6 0,03275672 MAD2L1, GMNN, GAS1, RBI, HPGD, APBB1 44,45583394 BP ALL regulation of cell cycle
GOTERM_ GO:0051726~regulation of LOC640611, DBF4, GMNN, GAS1, RBI, OBFC2A, CDK4, CDT1,
14 0,11462471 88,34388858 BP ALL cell cycle CCNE2, MAD2L1, BAX, JUN, APBB1, HPGD, CABLES1
GO:0010948~negative
GOTERM_
regulation of cell cycle 3 0,17246989 MAD2L1, GAS1, APBB1 96,46407279 BP ALL
process
GOTERM_ G0:0010564~regulation of
5 0,36526299 MAD2L1, DBF4, GAS1, APBB1, CDT1 99,96727598 BP ALL cell cycle process
GOTER _ GO:0007346~regulation of
5 0,57476855 MAD2L1, DBF4, GAS1, APBB1, CDT1 99,99997223 BP ALL mitotic cell cycle
Annotation Enrichment Score:
Cluster 27 1.0681358268020182
Gene
Category Term PValue Genes FDR
Count
DBF4, RASL2-9, TPD52L1, PTTGl, RBI, CCNGl, WEEl, SPC25,
GOTERM_ GO:0000278~mitotic cell
19 0,01438857 DCLREIA, MAD2L1, CCNB2, PLK2, CENPV, CAMK2D, SETD8, 22,5757463 BP_ALL cycle
MAPRE2, ID4, STMN1, CABLES1
DBF4, RASL2-9, PTTGl, CCNGl, SESN1, SPC25, CGREF1,
GOTERM_ GO:0022402~cell cycle CAMK2D, CABLES1, SYCE2, GAS2, TOPBPl, TPD52L1, GAS1,
27 0,01441123 22,60716393 BP_ALL process RBI, WEEl, MFN2, DCLREIA, REC8, CCNB2, MAD2L1, CENPV,
SETD8, ID4, MAPRE2, STM 1, APBB1
JUB, LOC640611, DBF4, E2F8, RASL2-9, PTTGl, CCNGl,
SESN1, CDT1, CCNE2, SPC25, CGREF1, CAMK2D, CABLES1,
GOTERM_ TXNIP, GMNN, SYCE2, TPD52L1, GAS2, TOPBPl, RBI, GAS1,
GO:0007049~cell cycle 38 0,01532954 23,87041205 BP ALL CDK4, APPL2, WEEl, MFN2, REC8, DCLREIA, MAD2L1,
CCNB2, PLK2, CENPV, MAPRE2, SETD8, ID4, PARD6G, STMN1,
APBB1, SEPT8
DBF4, RASL2-9, SYCE2, TOPBPl, TPD52L1, RBI, PTTGl,
GOTER _
GO:0022403~cell cycle phase 21 0,05951709 CCNGl, WEEl, SPC25, REC8, DCLREIA, MAD2L1, CCNB2, 66,15300833 BP_ALL
CAMK2D, CENPV, SETD8, MAPRE2, ID4, STMN1, CABLES1
LOC640611, RASL2-9, SYCE2, PTTGl, RBI, CDK4, CCNGl,
GOTERM_
GO:0051301~cell division 18 0,08213557 WEEl, CCNE2, SPC25, DCLREIA, NOTCH1, MAD2L1, CCNB2, 77,97738697 BP ALL CENPV, SETD8, MAPRE2, PARD6G, CABLES1
GOTER _ PEXllA, SPC25, DCLREIA, CCNB2, MAD2L1, RASL2-9, CENPV,
GO:004828S~organelle fission 12 0,20367725 98,2062379 BP ALL SETD8, MAPRE2, PTTGl, CCNGl, WEEl
GOTER _ SPC25, DCLREIA, CCNB2, MAD2L1, RASL2-9, CENPV, SETD8,
GO:0007067~mitosis 11 0,27353213 99,64532802 BP ALL MAPRE2, PTTGl, CCNGl, WEEl
GOTERM_ SPC25, DCLREIA, CCNB2, MAD2L1, RASL2-9, CENPV, SETD8,
GO:0000280~nuclear division 11 0,27353213 99,64532802
BP ALL MAPRE2, PTTGl, CCNGl, WEEl
GOTER _ GO:0000087~ phase of SPC25, DCLREIA, CCNB2, MAD2L1, RASL2-9, CENPV, SETD8,
11 0,29488882 99,79056765 BP ALL mitotic cell cycle MAPRE2, PTTGl, CCNGl, WEEl
GOTERM_ RASL2-9, SYCE2, TOPBPl, PTTGl, CCNGl, WEEl, SPC25, REC8,
GO:0000279~ phase 15 0,29826596 99,80758766 BP ALL DCLREIA, MAD2L1, CCNB2, CENPV, MAPRE2, SETD8, STMN1
Annotation Enrichment Score:
Cluster 28 1.0513476014055345
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0045637~regulation of
6 0,06113281 LM02, KLF10, FOX03, RBI, KITL, TOB2 67,1650356 BP ALL myeloid cell differentiation
GO:0045639~positive
GOTERM_
regulation of myeloid cell 4 0,08482189 KLF10, F0X03, RBI, KITL 79,08798012 BP_ALL
differentiation GO:0002763~positive
GOTERM_
regulation of myeloid 3 0,10055761 KLF10, RBI, KITL 84,6036963 BP_ALL
leukocyte differentiation
GO:0002761~regulation of
GOTERM_
myeloid leukocyte 4 0,11951223 KLF10, RBI, KITL, TOB2 89,4291302 BP_ALL
differentiation
Annotation Enrichment Score:
Cluster 29 1.0461022459573812
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0032869~cellular WDTC1, CAPNIO, SORBSl, BCARl, RHOQ, LOC100047575,
7 0,00854103 14,05274656 BP ALL response to insulin stimulus LPINl, IRS1
ME1, WDTC1, ACADS, BCARl, TGFBR2, RHOQ, IRS1, LPINl,
GOTERM_ GO:0009725~response to
14 0,0212805 TIMP3, WNT2, CAPNIO, SORBSl, LOC677317, ARSA, 31,59707506 BP_ALL hormone stimulus
LOC100047575, TES
ME1, WDTC1, ACADS, BCARl, TGFBR2, RHOQ, IRS1, LPINl,
GOTERM_ GO:0009719~response to
15 0,02262449 TIMP3, WNT2, SLC1A2, CAPNIO, SORBSl, LOC677317, ARSA, 33,23657092 BP_ALL endogenous stimulus
LOC100047575, TES
GO:0032870~cellular
GOTERM_ WDTC1, CAPNIO, SORBSl, BCARl, RHOQ, LOC100047575,
response to hormone 7 0,03363819 45,34273064 BP_ALL LPINl, IRS1
stimulus
GOTERM_ GO:0032868~response to WDTC1, CAPNIO, SORBSl, BCARl, RHOQ, LOC100047575,
7 0,03617568 47,82187491 BP ALL insulin stimulus LPINl, IRS1
GOTERM_ GO:0046324~regulation of
4 0,04288639 SLC1A2, CAPNIO, SORBSl, RHOQ 53,87700764 BP ALL glucose import
GOTER _ GO:0043434~response to WNT2, WDTC1, CAPNIO, SORBSl, BCARl, RHOQ,
9 0,04535528 55,93295182 BP ALL peptide hormone stimulus LOC100047575, LPINl, IRS1, TES
GOTERM_ GO:0043627~response to
5 0,04756017 WNT2, TGFBR2, ARSA, TIMP3, TES 57,69567829 BP ALL estrogen stimulus
GOTER _ GO:0010827~regulation of
4 0,04893451 SLC1A2, CAPNIO, SORBSl, RHOQ 58,76053481 BP_ALL glucose transport
GOTER _ GO:0048545~response to
6 0,10550245 WNT2, ACADS, TGFBR2, ARSA, TIIVIP3, TES 86,03156238 BP ALL steroid hormone stimulus
ME1, BCARl, PPARG, RHOQ, ACP5, PRDX2, CCL5, TIMP3,
GOTERM_ GO:0010033~response to TTC3, WNT2, SLC1A2, SORBSl, LOC677317, CYR61, TES,
27 0,16103616 95,49479051 BP_ALL organic substance WDTC1, ACADS, KLF10, TGFBR2, EPHX1, ANXA5, IRS1,
HERPUD2, LPINl, CAPNIO, FYN, ARSA, LOC100047575, PPP5C
PRKCZ, LIMAl, BCARl, RHOQ LPINl, TTL, WNT2, SPC25,
GOTERM_ GO:0007010~cytoskeleton
17 0,29066815 TUBA8, ARHGAP6, CAPNIO, SORBSl, MAPT, STMN1, CLN8, 99,76729693 BP_ALL organization
TES, RANBP10
GOTERM_ GO:0030029~actin filament- MY05A, LIMAl, ARHGAP6, CAPNIO, SORBSl, BCARl, RHOQ,
10 0,31708241 99,88092152 BP_ALL based process MY09B, APBB1, LPINl
GOTERM_ GO:0008286~insulin receptor
3 0,32845651 SORBSl, BCARl, IRS1 99,91147668 BP ALL signaling pathway
GOTERM_ GO:0007015~actin filament
4 0,41750075 LIMAl, ARHGAP6, SORBSl, BCARl 99,99281584 BP_ALL organization
GOTERM_ GO:0030879~mammary gland
5 0,4875933 WNT2, AR, TGFBR2, IRS1, TES 99,99925294 BP ALL development
GOTERM_ GO:0030036~actin
7 0,69372477 LIMAl, ARHGAP6, CAPNIO, SORBSl, BCARl, RHOQ LPINl 99,99999992 BP ALL cytoskeleton organization
Annotation Enrichment Score:
Cluster 30 1.0290241117114123
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0008643~carbohydrate G6PC, SORBSl, SLC2A2, SLC35B4, 2010001E11RIK, AI317395,
7 0,0388328 50,30397841 BP ALL transport FABP5
GOTERM_ GO:0015758~glucose
4 0,1104003 G6PC, SORBSl, SLC2A2, FABP5 87,32202667 BP_ALL transport
GOTERM_ GO:0008645~hexose
4 0,12889081 G6PC, SORBSl, SLC2A2, FABP5 91,25008637 BP ALL transport
GOTER _ GO:0015749~monosaccharide
4 0,13852004 G6PC, SORBSl, SLC2A2, FABP5 92,809195 BP ALL transport
Annotation Enrichment Score:
Cluster 31 1.0232897347528447
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0044242~cellular lipid
6 0,08419783 SMPDL3A, HEXA, HEXB, PNPLA2, DCI, HADHB 78,83479411 BP ALL catabolic process GOTERM_ GO:0030149~sphingolipid
3 0,10055761 SMPDL3A, HEXA, HEXB 84,6036963 BP ALL catabolic process
GOTERM_ GO:0046466~membrane lipid
3 0,10055761 SMPDL3A, HEXA, HEXB 84,6036963 BP ALL catabolic process
Annotation Enrichment Score:
Cluster 32 1.012795951900307
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051270~regulation of RTN4, JUB, EGFL7, RRAS2, BCARl, TEK, STMNl, TRIP6, IRSl,
10 0,03526269 46,94235455 BP ALL cell motion ADA
GOTERM_ GO:0030334~regulation of
9 0,03864324 RTN4, JUB, EGFL7, RRAS2, BCARl, TEK, TRIP6, IRSl, ADA 50,13065424 BP ALL cell migration
GOTERM_ GO:0040012~regulation of
9 0,09002583 RTN4, JUB, EGFL7, RRAS2, BCARl, TEK, TRIP6, IRSl, ADA 81,09079697 BP ALL locomotion
GOTER _ GO:0051272~positive
5 0,09105338 RRAS2, BCARl, STMNl, TRIP6, IRSl 81,46424291 BP ALL regulation of cell motion
RTN4, JUB, EGFL7, RAB3D, BCARl, RHOQ, MFGE8, PNPLA2,
GOTERM_ GO:0032879~regulation of
23 0,12992958 IRSl, ADA, CPT1A, APOA4, IGHG, SLC1A2, CD36, CAPN10, 91,43247776 BP_ALL localization
FCGR2B, SORBS1, BAX, RRAS2, TEK, STMNl, TRIP6
GOTERM_ GO:0030335~positive
4 0,20066415 RRAS2, BCARl, TRIP6, IRSl 98,0825616 BP ALL regulation of cell migration
GOTER _ GO:0040017~positive
4 0,27938198 RRAS2, BCARl, TRIP6, IRSl 99,69250626 BP ALL regulation of locomotion
Annotation Enrichment Score:
Cluster 33 0.995495581342468
Gene
Category Term PValue Genes FDR
Count
GO:0060742~epithelial cell
GOTERM_
differentiation involved in 4 0,01523175 AR, NOTCHl, PSAP, FOXAl, LOC100047556 23,73682363 BP_ALL
prostate gland development
GOTERM_ GO:0048754~branching TCF21, HHEX, AR, BMP2, NOTCHl, FOXAl, TGFBR2,
10 0,01571054 24,38878792 BP ALL morphogenesis of a tube LOC100047556, PLXND1, ENG, KDR
GOTER _ GO:0001763~morphogenesis TCF21, HHEX, AR, BMP2, NOTCH 1, EPHA7, FOXAl, TGFBR2,
11 0,03686316 48,47505118 BP ALL of a branching structure LOC100047556, PLXND1, ENG, KDR
GOTERM_ GO:0030324~lung WNT2, TCF21, HHEX, NOTCHl, LIPA, FOXAl, TGFBR2,
10 0,04302826 53,99755793 BP ALL development LOC100047556, ADA, KDR, TES
GOTERM_ GO:0030323~respiratory tube WNT2, TCF21, HHEX, NOTCHl, LIPA, FOXAl, TGFBR2,
10 0,04731076 57,49967652 BP ALL development LOC100047556, ADA, KDR, TES
BMP2, AR, LIPA, FOXAl, TGFBR2, ZEB2, ADA, KDR, WNT2,
GOTERM_ GO:0035295~tube
18 0,05205329 HHEX, TCF21, NOTCHl, TSCl, GATAD2A, LOC100047556, 61,08395385 BP ALL development
RARB, PLXND1, ENG, TES
GOTERM_ GO:0035239~tube BMP2, AR, TGFBR2, FOXAl, ZEB2, KDR, HHEX, TCF21,
13 0,05556044 63,54902569 BP ALL morphogenesis NOTCHl, TSCl, GATAD2A, LOC100047556, PLXND1, ENG
GOTERM_ GO:0060541~respiratory WNT2, TCF21, HHEX, NOTCHl, LIPA, FOXAl, TGFBR2,
10 0,07586624 75,16517388 BP ALL system development LOC100047556, ADA, KDR, TES
MY05A, ACP5, ZEB2, EGLNl, EPHB2, TCF21, INSIG2,
SMARCD3, GATAD2A, RARB, PLXND1, CAR2, SGPL1, AR,
GOTER _ GO:0009887~organ
32 0,12036875 BMP2, MY06, BHLHE22, SMAD7, GMNN, FOXAl, TGFBR2, 89,60921309 BP_ALL morphogenesis
GAS1, GAS6, MFN2, HHEX, NOTCHl, TSCl, BAX,
LOC100047556, NFIC, ENG, LRP4, PLEKHA1
MY05A, PPARA, ENPPl, PPARG, ZEB2, EGLNl, POSTN, TIMP3,
TCF21, ATG7, MTPN, GATAD2A, PAK1, RARB, PLXND1,
GOTERM_ GO:0009888~tissue
34 0,12326409 GPNMB, ANGPT2, CAR2, BMP2, AR, PSAP, SMAD7, KLF10, 90,19676083 BP_ALL development
FOXAl, KITL, CSRP3, KDR, HHEX, NOTCHl, TSCl, JUN,
LOC100047556, ENG, LRP4, BMP6
GOTERM_ GO:0002009~morphogenesis TCF21, HHEX, AR, BMP2, NOTCHl, TSCl, FOXAl, GATAD2A,
11 0,18925311 97,53734632 BP ALL of an epithelium ZEB2, LOC100047556, PLXNDl, CAR2
GOTERM_ GO:0030850~prostate gland
4 0,22266788 AR, NOTCHl, PSAP, FOXAl, LOC100047556 98,82861407 BP ALL development
BMP2, AR, PSAP, FOXAl, PPARG, ZEB2, KDR, HHEX, TCF21,
GOTERM_ GO:0060429~epithelium
15 0,24635026 NOTCHl, TSCl, JUN, GATAD2A, LOC100047556, PLXNDl, 99,32161898 BP_ALL development
CAR2
GOTERM_ GO:0048729~tissue BMP2, AR, SMAD7, FOXAl, EGLNl, ZEB2, HHEX, TCF21,
13 0,29S57155 99,79411897 BP ALL morphogenesis NOTCHl, TSCl, GATAD2A, LOC100047556, PLXNDl, CAR2
GOTERM_ GO:0O60562~epithelial tube
7 0,32035833 TCF21, HHEX, AR, BMP2, TSCl, GATAD2A, ZEB2 99,89061316 BP ALL morphogenesis
GOTERM_ GO:0048732~gland WNT2, HHEX, AR, NOTCHl, PSAP, FOXAl, TGFBR2,
10 0,44231698 99,99666909 BP ALL development LOC100047556, PLXNDl, IRSl, TES
GOTERM_ GO:0022612~gland
5 0,46927709 AR, NOTCHl, FOXAl, TGFBR2, LOC100047556, PLXNDl 99,99861119 BP ALL morphogenesis Annotation Enrichment Score:
Cluster 34 0.992615758759769
Gene
Category Term PValue Genes FDR
Count
GO:0006044~N-
GOTERM_
acetylglucosamine metabolic 3 0,07487328 RENBP, GNPDA1, NAGK 74,68982996 BP_ALL
process
GOTERM_ GO:0006041~glucosamine
3 0,07487328 RENBP, GNPDA1, NAGK 74,68982996 BP ALL metabolic process
GOTERM_ GO:0006040~amino sugar
3 0,18771501 RENBP, GNPDA1, NAGK 97,45354778 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 35 0.9922016569673757
Gene
Category Term PValue Genes FDR
Count
POSTN, FOX03, TTL, WNT2, INSIG2, SMARCD3, ANK3, ATG7,
H BB-B1, OLIG1, ATOH8, RARB, HBB-B2, SGPL1, MY06, IRS1,
VEGFB, HHEX, JUN, CAMK1, STMN1, EMCN, ENPP1, CH KB,
ACP5, ELK3, TIMP3, CD74, TTC3, ADA, EPHB2, TCF21, MEIS2,
TPN, PLXND1, GAL3ST1, BMP2, KI F3A, BHLH E22, SMAD7,
KLF10, FOXA1, TGFBR2, BPGM, GAS1, KITL, CSRP3, GAS6,
GOTER _ GO:0048731~system KDR, NOTCH l, EPHA7, TSCl, ENG, PLEKHA1, BMP6, RTN4,
103 0,02420663 35,11907989 BP_ALL development PPARA, H EXA, HEXB, PPARG, ZEB2, PRDX2, SLC1A2, TPPl,
MAPT, RHOC, SOX17, PAKl, CALCRL, ANGPT2, CABLES1,
CYR61, AR, EGFL7, RBI, GPR98, MFN2, UBD, CLN8, MY05A,
EGLN1, KIT, DTNBP1, CD9, GATAD2A, GPN B, CAR2, TES,
LIPA, PSAP, GMNN, ANXA4, RUFY3, HBA-Al, HBA-A2, CCNB2,
FYN, BAX, ARSA, ID4, BIK, LOC100047556, NFIC, IGFBP3,
APBB1, LRP4
MY05A, RTN4, H EXA, H EXB, ZEB2, TTL, TTC3, EPH B2, WNT2,
CD9, SLC1A2, TPPl, ANK3, MTPN, ATG7, MAPT, GATAD2A,
RHOC, OLIG1, ATOH8, PAKl, RARB, GAL3ST1, CABLES1, TES,
GOTERM_ GO:0007399~nervous system
47 0,0440773 BMP2, MY06, KIF3A, BHLHE22, FOXA1, TGFBR2, GAS1, 54,87977414 BP ALL development
RUFY3, GPR98, H HEX, EPHA7, NOTCH l, TSCl, FYN, BAX,
ARSA, CAMK1, ID4, LOC100047556, STMN 1, CLN8, APBB1,
LRP4
GNA12, POSTN, FOX03, TTL, WNT2, INSIG2, SMARCD3, ANK3,
ATG7, HBB-B1, OLIGl, AT0H8, RARB, HBB-B2, SGPL1, MY06,
IRS1, VEGFB, H H EX, JUN, CAMK1, STMN 1, EMCN, ENPP1,
CH KB, ACP5, ELK3, TIMP3, CD74, TTC3, ADA, EPHB2, TCF21,
MEIS2, MTPN, PLXND1, GAL3ST1, BMP2, KIF3A, BHLHE22,
SMAD7, LGALS1, KLF10, FOXA1, TGFBR2, BPGM, GAS1, KITL,
GOTERM_ GO:0048856~anatomical CSRP3, GAS6, KDR, EPHA7, NOTCH l, TSCl, CML5, ENG, CML3,
107 0,04560893 56, 13920442 BP ALL structure development PLEKHA1, BMP6, RTN4, PPARA, H EXA, HEXB, PPARG, ZEB2,
PRDX2, SLC1A2, TPPl, MAPT, RHOC, SOX17, PAKl, CALCRL,
ANGPT2, CABLES1, CYR61, AR, EGFL7, RBI, GPR98, MFN2,
UBD, CLN8, MY05A, EGLN1, KIT, DTNBP1, CD9, GATAD2A,
GPNMB, CAR2, TES, LIPA, PSAP, GMNN, ANXA4, RUFY3, HBA- Al, HBA-A2, CCNB2, FYN, BAX, ARSA, BIK, ID4,
LOC100047556, NFIC, IG FBP3, APBB1, LRP4
G NA12, POSTN, FOX03, TTL, WNT2, INSIG2, SMARCD3, ANK3,
ATG7, OLIGl, HBB-B1, RARB, AT0H8, HBB-B2, SGPL1, MY06,
ENC1, IRS1, VEGFB, HHEX, REC8, LRAT, GTF2IRD1, JUN,
CAMK1, STMN 1, EMCN, PLXNC1, ENPP1, CHKB, ACP5, ELK3,
TTC8, TIMP3, ADA, CD74, TTC3, EPH B2, TCF21, ADRB3,
MEIS2, MTPN, PTPLA, MBNL3, PLXND1, GAL3ST1, DNMT3A,
BMP2, KIF3A, BHLHE22, SMAD7, KLF10, LGALS1, FOXAl,
TGFBR2, BPGM, GAS1, CSRP3, KITL, GAS 6, KDR, EPHA7,
GQTERM_ GO:0032502~developmental NOTCH l, TSCl, PAPPA2, CML5, ENG, RERE, CML3, PLEKHA1,
132 0,05063953 60,04646637 BP_ALL process BMP6, RTN4, PPARA, HEXA, HEXB, HPS4, PPARG, PRDX2,
ZEB2, AMN, SLC1A2, TPPl, MAPT, GPX4, RHOC, PAKl, S0X17,
CALCRL, ANGPT2, CABLES1, CYR61, AR, EGFL7, RBI, LPIN1,
GPR98, MFN2, H IPK2, UBD, LOC100047575, CLN8, MY05A,
EGLN1, KIT, DTNBP1, MIF, CD9, GNPTAB, GATAD2A, GPNMB,
CAR2, TES, FZD8, WDTC1, LIPA, PSAP, GMNN, SNAI2, FZD4,
ANXA4, RUFY3, FZD7, HBA-Al, PEXllA, H BA-A2, CCNB2, FYN,
BAX, ARSA, BIK, ID4, LOC100047556, NFIC, IGFBP3, APBB1,
LRP4 GNA12, POSTN, FOX03, TTL, WNT2, INSIG2, SMARCD3, ANK3,
ATG7, 0LIG1, HBB-B1, ATOH8, RA B, HBB-B2, SGPL1, Y06,
ENC1, IRS1, VEGFB, HHEX, LRAT, GTF2IRD1, JUN, CA K1,
STMN1, EMCN, PLXNC1, ENPP1, CHKB, ACP5, ELK3, TIMP3,
ADA, CD74, TTC3, EPHB2, TCF21, EIS2, MTPN, PTPLA,
BNL3, PLXNDl, GAL3ST1, DN MT3A, BMP2, KIF3A, BH LHE22,
SMAD7, KLF10, FOXAl, TGFBR2, BPGM, GAS1, CSRP3, KITL,
GOTERM_ GO:0007275~multicellular GAS6, KDR, EPHA7, NOTCH1, TSC1, CML5, ENG, RERE, CM L3,
122 0,05200457 61,04862589 BP_ALL organismal development PLEKHA1, BMP6, RTN4, PPARA, H EXA, HEXB, PPARG, ZEB2,
PRDX2, AMN, SLC1A2, TPP1, APT, GPX4, RHOC, PAK1,
SOX17, CALCRL, ANGPT2, CABLES1, CYR61, AR, EGFL7, RBI,
GPR98, MFN2, H IPK2, UBD, LOC100047575, CLN8, MY05A,
EGLN 1, KIT, DTNBP1, CD9, GATAD2A, GPNMB, CAR2, TES,
FZD8, WDTC1, LIPA, PSAP, GMN N, SNAI2, ANXA4, FZD4,
RUFY3, FZD7, H BA-A1, HBA-A2, CCNB2, FYN, BAX, ARSA, BIK,
ID4, LOC100047556, NFIC, IGFBP3, APBB1, LRP4
RTN4, PPARA, PPARG, ZEB2, PRDX2, POSTN, FOX03, WNT2,
SLC1A2, INSIG2, S ARCD3, ATG7, H BB-B1, RARB, SOX17,
PAK1, H BB-B2, CALCRL, ANGPT2, CYR61, SGPL1, AR, MY06,
EGFL7, RBI, IRS1, GPR98, MFN2, VEGFB, HHEX, JUN, CLN8,
MY05A, EMCN, ENPP1, CHKB, ACP5, EGLN1, KIT, ELK3,
GOTERM_ GO:0048513~organ
82 0,07798111 DTNBP1, TIMP3, CD74, ADA, EPHB2, TCF21, MEIS2, MTPN, 76,14966461 BP_ALL development
GATAD2A, PLXNDl, GPNMB, CAR2, TES, BMP2, KIF3A, LIPA,
BH LHE22, SMAD7, PSAP, GMNN, KLF10, FOXAl, TGFBR2,
BPGM, GAS1, CSRP3, KITL, ANXA4, GAS6, KDR, HBA-A1, HBA- A2, NOTCH 1, CCN B2, TSC1, FYN, BAX, BIK, ID4,
LOC100047556, NFIC, ENG, LRP4, PLEKHA1, BMP6
RTN4, PPARG, H PS4, GNA12, ZEB2, FOX03, TTL, WNT2,
SMARCD3, ANK3, MAPT, ATG7, OLIG1, RHOC, ATOH8, RARB,
PAK1, SOX17, ANGPT2, SGPL1, AR, MY06, EGFL7, RBI, LPIN1,
GPR98, MFN2, VEGFB, HH EX, REC8, JUN, CAMK1, UBD,
GOTERM_ GO:0048869~cellular STMN1, CLN8, MY05A, KIT, TTC8, CD74, ADA, TTC3, EPH B2,
77 0,17718801 96,8035828 BP_ALL developmental process TCF21, CD9, ADRB3, GNPTAB, MTPN, GPNMB, TES, BMP2,
KIF3A, LIPA, BHLH E22, PSAP, LGALSl, FOXAl, TGFBR2, BPGM,
GAS1, CSRP3, KITL, RUFY3, KDR, HBA-A1, PEX11A, H BA-A2,
EPHA7, N0TCH1, TSC1, FYN, BAX, PAPPA2, ID4,
LOC100047556, IGFBP3, ENG, APBB1, LRP4, BMP6
RTN4, GNA12, ZEB2, INSIG2, SMARCD3, ANK3, SOX17, RARB,
ANGPT2, CYR61, SGPL1, AR, MY06, EG FL7, VEGFB, MFN2,
HHEX, STMN1, MY05A, EMCN, ACP5, EGLN1, ELK3, TIMP3,
GOTERM_ GO:0009653~anatomical ADA, EPH B2, CD9, TCF21, MTPN, GATAD2A, PLXNDl, CAR2,
54 0,17892626 96,92072399 BP_ALL structure morphogenesis BMP2, LIPA, KIF3A, BHLHE22, SMAD7, GMNN, FOXAl,
TGFBR2, GAS1, GAS6, KDR, NOTCHl, EPHA7, TSC1, BAX,
LOC100047556, NFIC, CML5, ENG, APBB1, CML3, LRP4,
PLEKHA1
RTN4, TTC3, TTL, EPHB2, WNT2, ANK3, ATG7, MAPT, MTPN,
GOTERM_ RHOC, OLIGl, RARB, PAK1, TES, BMP2, MY06, BH LHE22,
GO:0022008~neurogenesis 28 0, 18615068 97,36556615 BP_ALL FOXAl, GAS1, GPR98, NOTCHl, EPHA7, FYN, BAX, ID4,
LOC100047556, STMN 1, CLN8, APBBl
RTN4, PPARG, H PS4, GNA12, ZEB2, FOX03, TTL, WNT2,
SMARCD3, ANK3, MAPT, ATG7, OLIGl, RHOC, ATOH8, RARB,
PAK1, SOX17, ANGPT2, SGPL1, AR, MY06, EGFL7, RBI, LPIN1,
GPR98, VEGFB, HHEX, REC8, JUN, CAMK1, UBD, STMN1,
GOTERM_ GO:0030154~cell CLN8, MY05A, KIT, TTC8, CD74, ADA, TTC3, EPHB2, TCF21,
73 0,2080472 98,37230357 BP ALL differentiation ADRB3, G PTAB, MTPN, GPNMB, TES, BM P2, BH LHE22,
PSAP, LGALSl, FOXAl, TGFBR2, BPGM, GAS1, CSRP3, KITL,
RUFY3, KDR, HBA-A1, PEX11A, H BA-A2, EPHA7, NOTCH l,
TSC1, FYN, BAX, PAPPA2, ID4, LOC100047556, IGFBP3, ENG,
APBBl, LRP4, BMP6
Figure imgf000045_0001
GOTERM_ GO:0000165~MAPKKK
4 0,86133997 CD81, PRDX2, CD74, FGD4 100 BP ALL cascade
Annotation Enrichment Score:
Cluster 37 0.9808980455272152
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048041~focal adhesion
3 0,0413933 JUB, ARHGAP6, SORBS1 52,59009399 BP ALL formation
GOTERM_ GO:0034329~cell junction
4 0,05537447 CD9, JUB, ARHGAP6, SORBS1 63,42210117 BP ALL assembly
GOTERM_ GO:0007044~cell-substrate
3 0,11418496 JUB, ARHGAP6, SORBS1 88,24125646 BP ALL junction assembly
GOTERM_ GO:0034330~cell junction
4 0,14838386 CD9, JUB, ARHGAP6, SORBS1 94,13211677 BP ALL organization
GOTERM_ GO:0007160~cell-matrix
5 0,15585684 JUB, ARHGAP6, SORBS1, EPD 1, TEK 94,97769126 BP ALL adhesion
GOTERM_ GO:0031589~cell-substrate
5 0,21510509 JUB, ARHGAP6, SORBS1, EPDR1, TEK 98,6102521 BP ALL adhesion
Annotation Enrichment Score:
Cluster 38 0.959854055336618
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048771~tissue
6 0,04563134 LIPA, ENPP1, TPP1, BAX, ACP5, SPP2 56,1573834 BP ALL remodeling
GOTERM_ GO:0048871~multicellular
7 0,07622053 ADRB3, LIPA, PTGER3, TPP1, BAX, ACP5, KDR 75,3327296 BP ALL organismal homeostasis
GOTERM_ GO:0001894~tissue
5 0,15585684 LIPA, TPP1, BAX, ACP5, KDR 94,97769126 BP ALL homeostasis
GOTERM_ GO:0060249~anatomical
6 0,26700705 LIPA, LARGE, TPP1, BAX, ACP5, KDR 99,58467642 BP ALL structure homeostasis
Annotation Enrichment Score:
Cluster 39 0.907870539299038
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0008202~steroid CYB5R3, HSD17B11, OSBPL5, CYP46A1, FDPS, EBPL, STARD5,
13 0,03799236 49,53119626 BP ALL metabolic process G6PC, IIMSIG2, CYP7A1, OSBPL11, CLN8, CLN6
GOTERM_ GO:0016125~sterol metabolic
8 0,04187378 CYB5R3, EBPL, INSIG2, CYP46A1, CYP7A1, FDPS, CLN8, CLN6 53,00787638 BP ALL process
GOTERM_ GO:0008203~cholesterol
7 0,07219589 CYB5R3, INSIG2, CYP46A1, CYP7A1, FDPS, CLN8, CLN6 73,36499201 BP_ALL metabolic process
GOTERM_ GO:0006695~cholesterol
3 0,25004789 CYB5R3, INSIG2, FDPS 99,37803917 BP ALL biosynthetic process
GOTER _ GO:0006694~steroid
5 0,34606101 HSD17B11, CYB5R3, STARD5, INSIG2, FDPS 99,94461684 BP ALL biosynthetic process
GOTERM_ GO:0016126~sterol
3 0,35929408 CYB5R3, INSIG2, FDPS 99,9613961 BP ALL biosynthetic process
Annotation Enrichment Score:
Cluster 40 0.8826982586862604
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006639~acylglycerol
5 0,1041252 MOGAT2, G6PC, INSIG2, PNPLA2, PPAP2A 85,6469551 BP ALL metabolic process
GOTERM_ GO:0006638~neutral lipid
5 0,11799824 MOGAT2, G6PC, INSIG2, PNPLA2, PPAP2A 89,10359476 BP ALL metabolic process
GOTERM_ GO:0006662~glycerol ether
5 0,11799824 MOGAT2, G6PC, INSIG2, PNPLA2, PPAP2A 89,10359476 BP ALL metabolic process
GOTERM_ GO:0018904~organic ether
5 0,14020237 OGAT2, G6PC, INSIG2, PNPLA2, PPAP2A 93,05311953 BP ALL metabolic process
GOTERM_ GO:0006641~triglyceride
4 0,18986567 OGAT2, G6PC, INSIG2, PNPLA2 97,56998964 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 41 0.8797105995165208
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0022604~regulation of RTN4, FYN, MAPT, GNA12, RHOQ, GAS2, CDC42EP3, TTC3,
10 0,02018437 30,23188025 BP ALL cell morphogenesis TTL, EPHB2 GOTERM_ GO:0060284~regulation of RTN4, BMP2, FOXAl, TTC3, TTL, EPHB2, NOTCHl, BAX, MAPT,
13 0,03501647 46,70277806 BP ALL cell development ID4, RHOC, LOC100047556, BNL3, IGFBP3
GOTER _ GO:0045664~regulation of RTN4, NOTCHl, MAPT, FOXAl, RHOC, ID4, LOC100047556,
9 0,06385687 68,80693214 BP ALL neuron differentiation TTC3, TTL, EPHB2
GOTERM_ GO:0048638~regulation of
5 0,06748288 RTN4, AR, MAPT, TGFBR2, TTL 70,87256469 BP ALL developmental growth
GOTER _ GO:0001558~regulation of
8 0,09049922 RTN4, ZMAT3, MAPT, CD81, IGFBP3, APBB1, TTL, CYR61 81,26371453 BP ALL cell growth
GOTER _ GO:0050767~regulation of RTN4, BMP2, NOTCHl, MAPT, FOXAl, RHOC, ID4,
10 0,10210155 85,06367186 BP ALL neurogenesis LOC100047556, TTC3, TTL, EPHB2
GO:0045596~negative
GOTERM_ RTN4, NOTCHl, LM02, ENPP1, RHOC, PRDX2, ID4, MBNL3,
regulation of cell 12 0,14192983 93,2954513 BP_ALL CD74, TTC3, TOB2, EPHB2
differentiation
GOTERM_ GO:0030516~regulation of
3 0,14268634 RTN4, MAPT, TTL 93,39904429 BP ALL axon extension
GO:0010769~regulation of
GOTER _
cell morphogenesis involved 5 0,15585684 RTN4, MAPT, TTC3, TTL, EPHB2 94,97769126 BP_ALL
in differentiation
GOTERM_ GO:0051960~regulation of RTN4, BMP2, NOTCHl, MAPT, FOXAl, RHOC, ID4,
10 0,16798162 96,10976219 BP ALL nervous system development LOC100047556, TTC3, TTL, EPHB2
GO:0045665~negative
GOTERM_
regulation of neuron 4 0,16875118 NOTCHl, RHOC, ID4, TTC3 96,17280027 BP ALL
differentiation
GOTER _ GO:0050770~regulation of
4 0,22266788 RTN4, MAPT, TTL, EPHB2 98,82861407 BP_ALL axonogenesis
GO:0010721~negative
GOTERM_
regulation of cell 4 0,23384378 RTN4, ID4, TTC3, EPHB2 99,09287924 BP_ALL
development
GO:0010975~regulatlon of
GOTERM_
neuron projection 4 0,31404946 RTN4, MAPT, TTL, EPHB2 99,8712315 BP_ALL
development
GOTER _ GO:0031344~regulation of
4 0,42874495 RTN4, MAPT, TTL, EPHB2 99,99490758 BP ALL cell projection organization
GOTERM_ GO:0050768~negative
3 0,47620465 RTN4, ID4, EPHB2 99,99889871 BP ALL regulation of neurogenesis
Annotation Enrichment Score:
Cluster 42 0.8741359342132774
Gene
Category Term PValue Genes FDR
Count
BID, MRCl, CLN3, MY06, TGFBR2, DENNDIA, MFGE8, STAB2,
GOTER _ GO:0016044~membrane
19 0,0373329 MFN2, PLEKHF1, IGHG, CD9, CD36, FCGR2B, BAX, ATG7, 48,91690704 BP_ALL organization
RAB34, CLN8, LRP4
GOTERM_ GO:0010324~membrane MRCl, IGHG, CLN3, MY06, CD36, FCGR2B, RAB34, TGFBR2,
12 0,16532104 95,88419257 BP ALL invagination DENNDIA, MFGE8, STAB2, LRP4
GOTERM_ MRCl, IGHG, CLN3, MY06, CD36, FCGR2B, RAB34, TGFBR2,
GO:0006897~endocytosis 12 0,16532104 95,88419257 BP ALL DENNDIA, MFGE8, STAB2, LRP4
MY05A, VPS29, MRCl, CLN3, MY06, GNPDA1, RAB3D,
GOTERM_ GO:0016192~vesicle- TGFBR2, DENNDIA, MFGE8, VPS41, STAB2, ANKRD27, IGHG,
23 0,31239805 99,8656473 BP_ALL mediated transport AP2B1, CD36, FCGR2B, RAB34, SYTL4, MCOLN1, GGA2,
VPS26A, LRP4
Annotation Enrichment Score:
Cluster 43 0.8718159823540478
Gene
Category Term PValue Genes FDR
Count
BID, PRDX2, KIT, FOX03, CD74, ADA, CASP6, MTHFS, ATG7,
GOTERM_ GO:0043067~regulation of VNNl, RARB, DEDD2, CLN3, SGK3, KLFIO, CYCS, GASl, SNAI2,
33 0,04539059 55,96171605 BP_ALL programmed cell death KITL, CIDEC, CARD10, PLEKHF1, SERPINB9, EPHA7, NOTCHl,
CAPN10, NUPR1, BAX, HIPK2, BIK, IGFBP3, CLN8, APBB1
BID, PRDX2, KIT, FOX03, CD74, ADA, CASP6, MTHFS, ATG7,
GOTERM_ GO:0010941~regulation of VNNl, RARB, DEDD2, CLN3, SGK3, KLF10, CYCS, GASl, SNAI2,
33 0,04881126 58,66608222 BP_ALL cell death KITL, CIDEC, CARD10, PLEKHF1, SERPINB9, EPHA7, NOTCHl,
CAPN10, NUPR1, BAX, HIPK2, BIK, IGFBP3, CLN8, APBB1
BID, KLF10, CYCS, FOX03, CIDEC, PLEKHF1, CASP6, EPHA7,
GOTERM_ GO:0043065~positive
17 0,05744677 NOTCHl, CAPN10, NUPR1, BAX, HIPK2, BIK, RARB, IGFBP3, 64,81318952 BP_ALL regulation of apoptosis
APBB1
BID, PRDX2, FOX03, CD74, ADA, MTHFS, CASP6, ATG7, VNNl,
GOTERM_ GO:0042981~regulation of RARB, DEDD2, CLN3, SGK3, KLF10, CYCS, GASl, SNAI2, KITL,
32 0,06066783 66,87675075 BP_ALL apoptosis CIDEC, CARD10, PLEKHF1, SERPINB9, EPHA7, NOTCHl,
CAPN10, NUPR1, BAX, HIPK2, BIK, IGFBP3, CLN8, APBB1 GO:0043068~positive BID, KLF10, CYCS, F0XO3, CIDEC, PLEKHF1, CASP6, EPHA7,
GOTER _
regulation of programmed 17 0,0608565 NOTCHl, CAPNIO, NUPRl, BAX, HIPK2, BIK, RARB, IGFBP3, 66,99401293 BP_ALL
cell death APBB1
BID, KLF10, CYCS, FOX03, CIDEC, PLEKHF1, CASP6, EPHA7,
GOTERM_ GO:0010942~positive
17 0,06439479 NOTCHl, CAPNIO, NUPRl, BAX, HIPK2, BIK, RARB, IGFBP3, 69,12186837 BP ALL regulation of cell death
APBB1
GO:0043069~negative
GOTERM_ CLN3, SGK3, PRDX2, KIT, SNAI2, KITL, ADA, CD74, SERPINB9,
regulation of programmed 15 0,14569876 93,79676842 BP_ALL NOTCHl, BAX, ATG7, HIPK2, VNN1, CLN8
cell death
GOTERM_ GO:0060548~negative CLN3, SGK3, PRDX2, KIT, SNAI2, KITL, ADA, CD74, SERPINB9,
15 0,14816276 94,10516327 BP ALL regulation of cell death NOTCHl, BAX, ATG7, HIPK2, VNN1, CLN8
GOTER _ GO:0043066~negative CLN3, SGK3, PRDX2, SNAI2, KITL, CD74, ADA, SERPINB9,
14 0,20293421 98,17645794 BP ALL regulation of apoptosis NOTCHl, BAX, ATG7, HIPK2, VNN1, CLN8
GOTERM_ GO:0012502~induction of PLEKHF1, CASP6, NUPRl, BAX, KLF10, HIPK2, BIK, FOX03,
9 0,3994149 99,9876742 BP ALL programmed cell death CIDEC
GOTERM_ GO:0006917~induction of PLEKHF1, CASP6, NUPRl, BAX, KLF10, HIPK2, BIK, FOX03,
9 0,3994149 99,9876742 BP ALL apoptosis CIDEC
GO:0008629~induction of
GOTERM_
apoptosis by intracellular 3 0,43378855 NUPRl, BAX, HIPK2 99,99564559 BP_ALL
signals
GOTERM_
GO:0006916~anti-apoptosis 5 0,50564741 SERPINB9, SGK3, VNN1, PRDX2, SNAI2 99,99960342 BP ALL
Annotation Enrichment Score:
Cluster 44 0.8467237810756466
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0000226~microtubule WNT2, SPC25, PRKCZ, TUBA8, MAPT, STMNl, TTL, TES,
9 0,09367613 82,38614151 BP_ALL cytoskeleton organization RANBP10
GOTERM_ GO:0007017~microtubule- PRKCZ, KIF3A, KIF16B, TCTE3, TTL, WNT2, SPC25, TUBA8,
14 0,10587716 86,13450841 BP ALL based process DYNLL2, MAPT, KIFAP3, STMNl, RANBP10, TES
PRKCZ, LIMA1, BCAR1, RHOQ, LPIN1, TTL, WNT2, SPC25,
GOTERM_ GO:0007010~cytoskeleton
17 0,29066815 TUBA8, ARHGAP6, CAPNIO, SORBSl, MAPT, STMNl, CLN8, 99,76729693 BP_ALL organization
TES, RANBP10
Annotation Enrichment Score:
Cluster 45 0.8418451632264958
Gene
Category Term PValue Genes FDR
Count
GO:0006800~oxygen and
GOTERM_
reactive oxygen species 7 0,01307739 GPX4, FM02, GPX3, CYCS, MPV17, PRDX2, NDUFS1 20,73705261 BP_ALL
metabolic process
GOTERM_ GO:0042743~hydrogen
4 0,04893451 GPX4, GPX3, CYCS, PRDX2 58,76053481 BP ALL peroxide metabolic process
GOTERM_ GO:0042744~hydrogen
3 0,08743055 GPX4, GPX3, PRDX2 80,11573649 BP ALL peroxide catabolic process
GO:007030i~ceiigiar
G0TERM_
response to hydrogen 3 0,08743055 GPX4, GPX3, PRDX2 80,11573649 BP_ALL
peroxide
GO:0034614~cellular
GOTER _
response to reactive oxygen 3 0,17246989 GPX4, GPX3, PRDX2 96,46407279 BP_ALL
species
GOTERM_ GO:0034599~cellular
3 0,23433814 GPX4, GPX3, PRDX2 99,10315755 BP ALL response to oxidative stress
GOTERM_ GO:0042542~response to
3 0,26578565 GPX4, GPX3, PRDX2 99,5722873 BP_ALL hydrogen peroxide
GOTERM_ GO.0006979~response to
6 0,29956752 TXNIP, GPX4, GPX3, PRDX2, GPX7, CLN8 99,8137919 BP ALL oxidative stress
GOTERM_ GO:0000302~response to
3 0,44813695 GPX4, GPX3, PRDX2 99,99723225 B ALL reactive oxygen species
GOTERM_ GO:0010035~response to
5 0,54086927 ABCB1A, GPX4, GPX3, PRDX2, ASNA1 99,99989245 BP ALL inorganic substance
Annotation Enrichment Score:
Cluster 46 0.7721820302127351
Gene
Category Term PValue Genes FDR
Count MKRNl, LDHB, GNPDA1, HEXA, HEXB, PPP2R5C, PGAM1,
PRDX2, MYLIP, OGDH, DNASE1L3, DNASE1L1, USP18, TPP1,
SMPDL3A, CYP7A1, ATG7, GPX4, GPX3, NSMCE2, PDHA1,
FBX021, FAM176A, CLN3, AC02, HKDC1, ENCl, PNPLA2,
GOTER _ GO:0009056~catabolic G6PC, CD36, PIAS3, PKLR, DDB2, UCHL5, UBD, CLN8, PRODH,
72 2,65E-05 0,04676246 BP_ALL process CLN6, ENPP5, LOC100048346, ATG10, USP2, ENPP2, ABHD4,
UPP2, ASB13, ADA, DCI, HADHB, AKR1A4, DDHD2, CSAD,
OXCT1, PLA2G12A, IDH2, ENTPD2, LIPA, UFSPl, MAOA, CS,
CHI3L1, EPHX1, IDH3B, BPGM, DLAT, WIPI1, IDH3A, LYVE1,
ARSA, LIPG, FBX032, COMT1, UBE2E2
MKRNl, HEXA, HEXB, PPP2R5C, PRDX2, MYLIP, DNASE1L3,
DNASE1L1, USP18, S PDL3A, TPP1, GPX4, ATG7, GPX3,
NSMCE2, FBX021, FAM176A, CLN3, AC02, ENCl, PNPLA2,
GOTERM_ GO:0044248~cellular CD36, PIAS3, DDB2, UCHL5, UBD, CLN8, CLN6, PRODH,
53 0,00352022 6,03593636 BP_ALL catabolic process ENPP5, LOC100048346, ATGIO, USP2, UPP2, ASB13, DCI,
ADA, HADHB, AKR1A4, CSAD, OXCTl, IDH2, ENTPD2, UFSPl,
MAOA, CS, EPHX1, IDH3B, WIPI1, IDH3A, ARSA, FBX032,
COMTl, UBE2E2
LOC100048346, MKRNl, ATGIO, USP2, PPP2R5C, MYLIP,
GOTERM_ GO:0009057~macromolecijle ASB13, DNASE1L3, DNASE1L1, USP18, ATG7, NSMCE2,
27 0,63645166 99,99999825 BP_ALL catabolic process FBX021, CLN3, UFSPl, ENCl, CHI3L1, LYVE1, G6PC, CD36,
PIAS3, UCHL5, DDB2, UBD, FBX032, CLN8, UBE2E2, CLN6
MKRNl, LOC100048346, ERMPl, SOLH, ATGIO, USP2, CNDP2,
PPP2R5C, MME, CTSA, ASB13, MYLIP, PRSS8, CASP6, USP18,
GOTERM_ TPP1, ATG7, PITRM1, NSMCE2, FBX021, CFD, DPP7, DPP4,
GO:0006508~proteolysis 40 0,77651425 100 BP_ALL CTSZ, UFSPl, ENCl, MMP15, MMP12, IGHG, CAPNIO, PIAS3,
BACE1, UCHL5, DDB2, UBD, PAPPA2, FBX032, NLN, CTSB,
UBE2E2, PMPCB
LOC100048346, MKRNl, ATGIO, UFSPl, USP2, ENCl,
GO:0044265~cellular
GOTERM_ PPP2R5C, MYLIP, ASB13, DNASE1L3, DNASE1L1, USP18,
macromolecule catabolic 23 0,79248887 100 BP_ALL CD36, PIAS3, ATG7, UCHL5, DDB2, UBD, NSMCE2, FBX032,
process
FBX021, CLN8, UBE2E2, CLN6
GO:0019941~modification- LOC100048346, MKRNl, ATGIO, UFSPl, USP2, ENCl,
GOTER _
dependent protein catabolic 18 0,86005922 PPP2R5C, MYLIP, ASB13, USP18, PIAS3, ATG7, UCHL5, DDB2, 100 BP_ALL
process NSMCE2, UBD, FBX032, FBX021, UBE2E2
GO:0043632~modification- LOC100048346, MKRNl, ATGIO, UFSPl, USP2, ENCl,
GOTERM_
dependent macromolecule 18 0,86005922 PPP2R5C, MYLIP, ASB13, USP18, PIAS3, ATG7, UCHL5, DDB2, 100 BP_ALL
catabolic process NSMCE2, UBD, FBX032, FBX021, UBE2E2
LOC100048346, MKRNl, ATGIO, UFSPl, USP2, ENCl,
GOTERM_ GO:0044257~cellular protein
19 0,86441225 PPP2R5C, MYLIP, ASB13, USP18, PIAS3, ATG7, UCHL5, DDB2, 100 BP_ALL catabolic process
UBD, NSMCE2, FBX032, FBX021, CLN8, UBE2E2
LOC100048346, MKRNl, ATGIO, UFSPl, USP2, ENCl,
GOTER _ GO:0030163~protein
19 0,89733732 PPP2R5C, MYLIP, ASB13, USP18, PIAS3, ATG7, UCHL5, DDB2, 100 BP_ALL catabolic process
UBD, NSMCE2, FBX032, FBX021, CLN8, UBE2E2
GO:0051603~proteolysis LOC100048346, MKRNl, ATGIO, UFSPl, USP2, ENCl,
GOTERM_
involved in cellular protein 18 0,90538728 PPP2R5C, MYLIP, ASB13, USP18, PIAS3, ATG7, UCHL5, DDB2, 100 BP_ALL
catabolic process NSMCE2, UBD, FBX032, FBX021, UBE2E2
Annotation Enrichment Score:
Cluster 47 0.7634084172686628
Gene
Category Term PValue Genes FDR
Count
ARL6IP1, MY05A, BID, VPS29, GRPEL2, RASL2-9, HPS4,
GOTER _ GO:0046907~intracellular MY09B, CD74, AP2B1, DYNLL2, MCOLN1, TXNIP, RAMP2,
27 0,03960744 51,00634825 BP ALL transport MY06, VPS41, TIMM44, MFN2, PLEKHF1, ANKRD27, AAAS,
BAX, SYTL4, CAMK1, APBB1, GGA2, VPS26A
ARL6IP1, VPS29, BID, GRPEL2, ATGIO, RAB3D, SLC15A2,
ZMAT3, HEXA, HPS4, HEXB, PPARG, RASL2-9, SNX16, AMN,
CD74, APOA4, AP2B1, STARD5, RAB43, GNPTAB, ATG7,
GOTERM_ GO:0033036~macromolecule
47 0,09383729 KIFAP3, TXNIP, RAMP2, CPT1B, OSBPL5, MY06, VPS41, 82,44135648 BP_ALL localization
TIMM44, GLTP, MFN2, PITPNMl, RAB30, CD36, BAX, RAB34,
TOMM40L, RAB17, CD81, SYTL4, OSBPL11, SNX12, SNX30,
VPS26A, GGA2, LRP4
ARL6IP1, VPS29, BID, GRPEL2, ATGIO, RAB3D, SLC15A2,
ZMAT3, HPS4, SNX16, RASL2-9, AMN, CD74, AP2B1, RAB43,
GOTERM_ GO:0008104~protein GNPTAB, ATG7, KIFAP3, TXNIP, RAMP2, MY06, VPS41,
38 0,17620001 96,73514034 BP_ALL localization TIMM44, MFN2, PITPNMl, RAB30, CD36, BAX, RAB34,
TOMM40L, RAB17, CD81, SYTL4, SNX12, SNX30, VPS26A,
GGA2, LRP4
Figure imgf000050_0001
GO:0031112~positive
GOTERM_ regulation of microtubule
3 0,06296037 WNT2, MAPT, TES 68,27532436 BP_ALL polymerization or
depolymerization
GO:0031109~microtubule
GOTERM_
polymerization or 3 0,07487328 WNT2, STMNl, TES 74,68982996 BP_ALL
depolymerization
GOTERM_ GO:0000226~microtubule WNT2, SPC25, PRKCZ, TUBA8, MAPT, STMNl, TTL, TES,
9 0,09367613 82,38614151 BP ALL cytoskeleton organization RANBP10
GOTERM_ GO:0032886~regulation of
5 0,11799824 WNT2, MAPT, MTAP4, STMNl, TES 89,10359476 BP ALL microtubule-based process
GO:0031111~negative
GOTERM_ regulation of microtubule
3 0,14268634 MAPT, MTAP4, STMNl 93,39904429 BP_ALL polymerization or
depolymerization
GO:0032273~positive
GOTERM_
regulation of protein 3 0,18771501 WNT2, MAPT, TES 97,45354778 BP_ALL
polymerization
GO:0010639~negative
GOTERM_
regulation of organelle 5 0,26062447 LIMAl, MAD2L1, MAPT, MTAP4, STMNl 99,51598237 BP_ALL
organization
GO:0031334~positive
GOTERM_
regulation of protein complex 3 0,26578565 WNT2, MAPT, TES 99,5722873 BP_ALL
assembly
GO:0051495~positive
GOTERM_
regulation of cytoskeleton 3 0,29722846 WNT2, MAPT, TES 99,80250301 BP_ALL
organization
GO:0051494~negative
GOTERM_
regulation of cytoskeleton 4 0,32563927 LIMAl, MAPT, MTAP4, STMNl 99,90468614 BP_ALL
organization
GOTERM_ GO:0051493~regulation of
6 0,39965959 WNT2, LIMAl, MAPT, MTAP4, STMNl, TES 99,98776255 BP ALL cytoskeleton organization
GO:0051130~positive
GOTERM_
regulation of cellular 7 0,40290135 WNT2, IGHG, SORBS1, FCGR2B, MAPT, MFGE8, TES 99,98887817 BP_ALL
component organization
GOTERM_ GO:0032271~regulation of
4 0,42874495 WNT2, MAPT, STMNl, TES 99,99490758 BP_ALL protein polymerization
GO:0043242~negative
GOTERM_
regulation of protein complex 3 0,43378855 LIMAl, MAPT, MTAP4 99,99564559 BP_ALL
disassembly
GOTERM_ GO:0033043~regulation of
8 0,46651754 WNT2, LIMAl, MAD2L1, MAPT, MTAP4, CENPV, STMNl, TES 99,99847803 BP ALL organelle organization
GOTERM_ GO:0043254~regulation of
4 0,51538935 WNT2, MAPT, STMNl, TES 99,99972092 BP_ALL protein complex assembly
GOTERM_ GO:0043244~regulation of
3 0,54240679 LIMAl, MAPT, MTAP4 99,99989863 BP ALL protein complex disassembly
GO:0010638~positive
GOTERM_
regulation of organelle 3 0,64625683 WNT2, MAPT, TES 99,99999892 BP_ALL
organization
GO:0044087~regulation of
GOTERM_
cellular component 4 0,7256992 WNT2, MAPT, STMNl, TES 99,99999999 BP ALL
biogenesis
Annotation Enrichment Score:
Cluster 50 0.748499279892857
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0019400~alditol
4 0,08482189 GPD2, GALK1, MOGAT2, GDPD1 79,08798012 BP ALL metabolic process
GOTERM_ GO:0006071~glycerol
3 0,25004789 GPD2, MOGAT2, GDPD1 99,37803917 BP_ALL metabolic process
GOTERM_ GO:0019751~polyol
4 0,26789897 GPD2, GALK1, MOGAT2, GDPD1 99,59350875 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 51 0.7350457658895937
Gene
Category Term PValue Genes FDR
Count PRDX2, PRKG2, WIMT2, PAKl, NDUFSl, PIK3C2G, SGK3, PI4KA,
CDK4, WEE1, ATP6V1A, G6PC, CD81, H IPK2, CAMK1, PPP5C,
FRK, PRKCZ, LOC640611, TRIB3, ACP5, KIT, ATP6V0C-PS2,
GOTER _ GO:0D06796~phosphate
51 0,01268117 ATP6V1B2, ATP6V0B, CD74, EPHB2, ATP6V0C, GALK1, SBK1, 20, 17337511 BP_ALL metabolic process
GNPTAB, PTPLA, TEK, CA K2D, PPAP2A, TES, FGD4, GPD2,
PTPRB, PDK1, PDK2, SMAD7, TGFBR2, TAOK3, PDK4, KDR,
DUSP3, EPHA7, PTP4A3, RPS6KA1, PLK2, FYN, IGFBP3
PRDX2, PRKG2, WNT2, PAKl, NDUFSl, PIK3C2G, SGK3, PI4KA,
CDK4, WEE1, ATP6V1A, G6PC, CD81, HIPK2, CAMK1, PPP5C,
FRK, PRKCZ, LOC640611, TRIB3, ACP5, KIT, ATP6V0C-PS2,
GOTERWL GO:0006793~phosphorus
51 0,01268117 ATP6V1B2, ATP6V0B, CD74, EPHB2, ATP6V0C, GALK1, SBK1, 20, 17337511 BP_ALL metabolic process
GNPTAB, PTPLA, TEK, CAMK2D, PPAP2A, TES, FGD4, GPD2,
PTPRB, PDK1, PDK2, SMAD7, TGFBR2, TAOK3, PDK4, KDR,
DUSP3, EPHA7, PTP4A3, RPS6KA1, PLK2, FYN, IGFBP3
PRKCZ, FRK, LOC640611, TRIB3, PRDX2, PRKG2, ATP6V0C- PS2, KIT, ATP6V1B2, CD74, ATP6V0B, EPH B2, WNT2,
GOTERM_ ATP6V0C, GALK1, SBK1, GNPTAB, TEK, CAMK2D, PAKl,
GO:0016310~phosphorylation 42 0,02657591 37,84477166 BP_ALL NDU FSl, TES, FGD4, PDK1, PDK2, PIK3C2G, SGK3, SMAD7,
PDK4, TGFBR2, TAOK3, PI4KA, CDK4, WEE1, KDR, ATP6V1A,
EPHA7, PLK2, RPS6KA1, FYN, HIPK2, CD81, CAMK1, IGFBP3
FRK, PRKCZ, LOC640611, TRIB3, PRDX2, PRKG2, KIT, CD74,
EPH B2, WNT2, SBK1, TEK, CAMK2D, PAKl, FGD4, TES, PDK1,
GOTERM_ GO:0006468~protein amino
33 0,16867024 PDK2, SGK3, S AD7, PDK4, TAOK3, TGFBR2, CDK4, WEE1, 96,16621603 BP_ALL acid phosphorylation
KDR, EPHA7, PLK2, RPS6KA1, FYN, CD81, HIPK2, CAMK1,
IGFBP3
H LCS, PRDX2, PRKG2, TTL, WNT2, USP18, ST3GAL3, P4HA2,
ATG7, NSMCE2, PAKl, SGK3, PIGQ, CDK4, PIGP, WEE1,
ST6GALNAC2, PIAS3, CD81, HIPK2, CAM Kl, PPP5C,
LOC100048346, PRKCZ, FRK, ATG10, FUT8, RAB3D,
GOTERM_ GO.0006464~protein
57 0,34101825 LOC640611, TRIB3, ST8SIA3, KIT, CD74, EPH B2, SBK1, TEK, 99,93657268 BP ALL modification process
CAMK2D, PPAP2A, TES, FGD4, PTPRB, PDK1, PDK2, SMAD7,
PDK4, TAOK3, TGFBR2, KDR, 2410022L05RIK, EPHA7, DUSP3,
PLK2, RPS6KA1, PTP4A3, FYN, ST8SIA4, IGFBP3, APBB1,
UBE2E2
HLCS, PRDX2, PRKG2, TTL, WNT2, USP18, ST3GAL3, P4HA2,
ATG7, NSMCE2, PAKl, SGK3, PIGQ, CDK4, PIGP, WEE1,
ST6GALNAC2, PIAS3, CD81, HIPK2, CAMKl, PPP5C,
LOC100048346, PRKCZ, FRK, ATG10, FUT8, RAB3D,
GOTERM_ GO:0043412~biopolymer
58 0,43016214 LOC640611, TRIB3, ST8SIA3, KIT, CD74, EPHB2, SBK1, TEK, 99,99512607 BP_ALL modification
CAMK2D, PPAP2A, TES, FGD4, PTPRB, PDK1, PDK2, DNMT3A,
SMAD7, PDK4, TAOK3, TGFBR2, KDR, 2410022L05RIK, EPHA7,
DUSP3, PLK2, RPS6KA1, PTP4A3, FYN, ST8SIA4, IGFBP3,
APBB1, UBE2E2
LOC100048346, PRKCZ, FRK, RAB3D, LOC640611, TRIB3,
PRDX2, PRKG2, KIT, CD74, EPHB2, WNT2, USP18, SBK1, TEK,
GO:0043687~post- CAMK2D, NSMCE2, PAKl, PPAP2A, TES, FGD4, PTPRB, PDK1,
GOTERM_
translational protein 45 0,53295092 PDK2, SG K3, SMAD7, PDK4, TGFBR2, TAOK3, CDK4, WEE1, 99,99985455 BP_ALL
modification KDR, 241O022LO5RIK, EPHA7, DUSP3, PLK2, PTP4A3,
RPS6KA1, FYN, PIAS3, H IPK2, CD81, CAMKl, IGFBP3, APBB1,
UBE2E2, PPP5C
MKRN1, GRPEL2, CNDP2, RPL13, PPP2R5C, PRKG2, MYLIP,
TTL, WNT2, ST3GAL3, ATG7, CFD, FBX021, ENC1, WEE1,
IGHG, PIAS3, BACE1, CAMKl, PPP5C, LOC100048346, ERMP1,
EIF4E3, FARS2, MME, CTSA, ST8SIA3, ASB13, CD74, EPH B2,
SBK1, TEK, FGD4, UFSP1, SMAD7, TAOK3, TGFBR2, KDR,
2410022L05RIK, EPHA7, PLK2, ST8SIA4, PAPPA2, FBX032,
GOTERM_ GO:0019538~protein UBE2E2, SOLH, HEXB, PRDX2, H LCS, CASP6, USP18, P4HA2,
101 0,85878303 100 BP_ALL metabolic process TPP1, BAG 2, NSMCE2, PAKl, DPP7, DPP4, CLN3, CTSZ, SGK3,
MMP15, PIGQ, CDK4, PIGP, MMP12, ST6GALNAC2, CAPN10,
H IPK2, CD81, UCHL5, DDB2, UBD, CTSB, CLN8, PMPCB,
PRKCZ, FRK, ATG10, RAB3D, FUT8, LOC640611, USP2, TRIB3,
KIT, PRSS8, PET112L, PITRMl, CAMK2D, TORIB, PPAP2A, TES,
PTPRB, PDK1, PDK2, PDK4, DUSP3, RPS6KA1, PTP4A3, FYN,
N LN, IGFBP3, APBB1 MKRN1, GRPEL2, RPL13, HEXB, PPP2R5C, PRDX2, HLCS,
MYLIP, PRKG2, TTL, WNT2, USP18, ST3GAL3, P4HA2, ATG7,
NSMCE2, PAKl, FBX021, SGK3, ENC1, CDK4, PIGQ, PIGP,
ST6GALNAC2, WEE1, PIAS3, CD81, HIPK2, DDB2, UCHL5,
CAMK1, UBD, CLN8, PPP5C, LOC100048346, PR CZ, FRK,
GOTERM_ GO:0044267~cellular protein
77 0,9219808 EIF4E3, ATG10, FUT8, RAB3D, LOC640611, USP2, FARS2,
BP_ALL 100
metabolic process
TRIB3, ST8SIA3, KIT, ASB13, CD74, EPHB2, PET112L, SBK1,
TEK, CAMK2D, TOR1B, PPAP2A, FGD4, TES, PDK1, PTPRB,
PDK2, UFSP1, SMAD7, PDK4, TAOK3, TGFBR2, KDR,
2410022L05RIK, EPHA7, DUSP3, PLK2, RPS6KA1, PTP4A3,
FYN, ST8SIA4, FBX032, IGFBP3, APBB1, UBE2E2
MKRN1, GRPEL2, RPL13, DBF4, PPP2R5C, BBX, MPV17,
TCEAL8, MYLIP, PRKG2, PTTGl, LOC100045031, DNASE1L3,
TCEALl, TTL, DNASEILI, WNT2, APOA4, ST3GAL3, SMARCD3,
ATG7, OLIG1, ZFP503, RARB, ATOH8, FBX021, PABPN1,
RREB1, ENC1, ZFP467, TOPBP1, HDAC11, PPARGC1A,
PPARGC1B, WEE1, HHEX, DCLRE1A, CD36, PIAS3, GTF2IRD1,
JUN, BACE1, CAMK1, PPP5C, LOC100048346, EIF4E3,
RAG1AP1, FARS2, ST8SIA3, ASB13, ELK3, OBFC2A, CD74,
EPHB2, TCF21, SBK1, RAD51L1, TEK, FGD4, DNMT3A,
GO:0044260~cellular BHLHE22, UFSP1, S AD7, KLF10, FOXA1, TGFBR2, TAOK3,
GOTERM_
rnacromolecule metabolic 146 0,99998727 PPFIBP2, LOC280487, KDR, 2410022L05RIK, EPHA7, NOTCHl, 100 BP_ALL
process PLK2, ST8SIA4, FBX032, UBE2E2, RERE, HLF, PPARA, HEXB,
PPARG, E2F8, HLCS, PRDX2, ZEB2, CDT1, CCNE2, USP18,
P4HA2, HSF2, GPX4, CHST14, NSMCE2, PAKl, SOX17, DEDD2,
CLN3, AR, SSBP3, SGK3, RBI, CDK4, PIGQ, PIGP, ST6GALNAC2,
DNASE2B, G6PC, CYP4A31, HIPK2, CD81, UCHL5, DDB2, UBD,
CLN8, CLN6, FRK, PRKCZ, ATG10, RAB3D, FUT8, USP2,
LOC640611, TRIB3, KIT, SEC14L2, PET112L, TOR1B, CAMK2D,
GATAD2A, PPAP2A, TES, PDK1, PTPRB, TXNIP, PDK2, PDK4,
SNAI2, CYP4A10, DUSP3, PTP4A3, LARGE, RPS6KA1, FYN,
GYG, SETD8, LOC100047556, NFIC, IGFBP3, APBB1, LRP4
Annotation Enrichment Score:
Cluster 52 0.7231382593955339
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009166~nucleotide
4 0,13852004 ENPP5, UPP2, ENTPD2, ADA 92,809195 BP ALL catabolic process
GO:0034655~nucleobase,
GOTERM_
nucleoside, nucleotide and 4 0,18986567 ENPP5, UPP2, ENTPD2, ADA 97,56998964 BP_ALL
nucleic acid catabolic process
GO:0034656~nucleobase,
GOTERM_
nucleoside and nucleotide 4 0,18986567 ENPP5, UPP2, ENTPD2, ADA 97,56998964 BP_ALL
catabolic process
GOTERM_ GO:0044270~nitrogen
4 0,25647289 ENPP5, UPP2, ENTPD2, ADA 99,46569096 BP_ALL compound catabolic process
Annotation Enrichment Score:
Cluster 53 0.6934703789735349
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0048738~cardiac muscle
6 0,08929197 TSC1, SMAD7, ATG7, EGLN1, RARB, CSRP3 80,81975541 BP ALL tissue development
GOTERM_ GO:0042692~muscle cell TSC1, SMARCD3, LGALS1, MTPN, ATG7, RBI, PAKl, RARB,
9 0,11731726 88,9541085 BP_ALL differentiation LRP4
GOTER _ GO:0007507~heart B P2, KIF3A, SMAD7, TGFBR2, EGLN1, CSRP3, HHEX,
14 0,14339249 93,49437859 BP ALL development NOTCHl, TSC1, S ARCD3, ATG7, RARB, CALCRL, ENG
GOTERM_ GO:0035051~cardiac cell
4 0,15846623 BMP2, TSC1, ATG7, RARB
BP_ALL differentiation 95,24483273
GOTERM_ GO:0051146~striated muscle
7 0,1688039 TSC1, MTPN, ATG7, RBI, PAKl, RARB, LRP4 96,17708395 BP ALL cell differentiation
GOTERM_ GO:0007517~muscle organ TSC1, SMAD7, CHKB, ATG7, EGLN1, PAKl, RARB, DTNBP1,
11 0,20322118 98,18801382 BP_ALL development ENG, CSRP3, LRP4
GOTERM_ GO:0060537~muscle tissue
9 0,2101522 TSC1, SMAD7, ATG7, EGLN1, PAKl, RARB, ENG, CSRP3, LRP4 98,4470172 BP ALL development
GOTERM_ GO:0014706~striated muscle
8 0,28225751 TSC1, SMAD7, ATG7, EGLN1, PAKl, RARB, CSRP3, LRP4 99,71346369 BP ALL tissue development
GOTERM_ GO:0055007~cardiac muscle
3 0,32845651 TSC1, ATG7, RARB 99,91147668 BP ALL cell differentiation
GOTERM_ GO:0055001~muscle cell
3 0,73055009 ATG7, PAKl, LRP4 99,99999999 BP ALL development Annotation Enrichment Score:
Cluster 54 0.6852839623369967
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0080135~regulation of
7 0,09355839 SH3RF1, CLN3, HIPK2, ZEB2, HBB-B1, HBB-B2, APBB1, FGD4 82,34570222 BP ALL cellular response to stress
GOTERM_ GO:0043408~regulation of
8 0,09454437 SH3RF1, ADRB3, AR, PSAP, HIPK2, ZEB2, FGF21, FGD4 82,68167781 BP ALL MAPKKK cascade
GOTERM_ GO:0080134~regulation of CLN3, SH3RF1, TGFBR2, ZEB2, ADA, IGHG, FCGR2B, GPX4,
12 0,16532104 95,88419257 BP ALL response to stress HIPK2, HBB-B1, HBB-B2, APBB1, FGD4
G0TERM_ GO:0032101~regulation of
7 0,26205335 IGHG, CLN3, PPARA, FCGR2B, GPX4, TGFBR2, ADA 99,53223321 BP ALL response to external stimulus
GOTERM_ GO:0046328~regulation of
4 0,29090939 SH3RF1, HIPK2, ZEB2, FGD4 99,76869015 BP ALL JNK cascade
GO:0070302~regulation of
GOTERM_
stress-activated protein 4 0,3024691 SH3RF1, HIPK2, ZEB2, FGD4 99,82695051 BP_ALL
kinase signaling pathway
GOTERM_ GO:0010627~regulation of
8 0,4733008 SH3RF1, ADRB3, AR, PSAP, HIPK2, ZEB2, FGF21, FGD4 99,9987858 BP ALL protein kinase cascade
Annotation Enrichment Score:
Cluster 55 0.6803130759063486
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009110~vitamin
4 0,11951223 NAMPT, AKR1A4, PDXK, RDH16 89,4291302 BP ALL biosynthetic process
GOTERM_ G0:0006766~vitamin
6 0,16181831 NAMPT, AKR1A4, PDXK, LRAT, RDH16, RETSAT 95,56836856 BP ALL metabolic process
GOTERM_ G0:0042364~water-soluble
3 0,23433814 NAMPT, AKR1A4, PDXK 99,10315755 BP ALL vitamin biosynthetic process
GOTERM_ GO:0006767~water-soluble
3 0,41924194 NAMPT, AKR1A4, PDXK 99,99318567 BP ALL vitamin metabolic process
Annotation Enrichment Score:
Cluster 56 0.6797464456192237
Gene
Category Term PValue Genes FDR
Count
MY05A, GABRD, CLN3, MY06, SLC25A4, HEXA, MAOA, HEXB,
GOTERM_ GO:0019226~transmission of
18 0,01424866 WNT2, P2RX4, CD9, HNMT, TSCl, FYN, COMT1, CLN8, 22,38148337 BP_ALL nerve impulse
GAL3ST1, TES
MY05A, HEXA, HEXB, SNX16, WNT2, CD9, SLC1A2, HNMT,
GOTERM_ GO:0007154~cell GAL3ST1, TES, GABRD, CLN3, PIK3C2G, MY06, SLC25A4,
29 0,02686731 38,17243715 BP_ALL communication SGK3, MAOA, FOXAl, KIF16B, IRSl, GPR98, P RX4, TSCl, FYN,
STAB1, LOC100047556, SNX30, SNX12, CLN8, COMT1
GOTERM_ GO:0001505~regulation of
6 0,11705757 CLN3, SLC25A4, HNMT, MAOA, COMT1, CLN8 88,89659387 BP ALL neurotransmitter levels
G0TERM_ GO:0007268~synaptic GABRD, WNT2, MY05A, CLN3, P2RX4, MY06, SLC25A4,
12 0,12737785 90,97787313 BP ALL transmission HNMT, MAOA, COMT1, CLN8, TES
GOTERM_ GO:0007601~visual
8 0,13039832 MY05A, UNC119, PDE6D, LRAT, DTNBPl, CLN8, GPR98, CLN6 91,51360028 BP ALL perception
GOTERM_ GO:0050953~sensory
8 0,13530137 MYOSA, UNC119, PDE6D, LRAT, DTNBPl, CLN8, GPR98, CLN6 92,31983157 BP ALL perception of light stimulus
GABRD, MY05A, CLN3, MY06, SLC25A4, MAOA, FOXAl, IRSl,
GOTERM_ GO:0007267~cell-cell
15 0,3309203 WNT2, P2RX4, HNMT, STAB1, LOC100047556, COMT1, CLN8, 99,91703866 BP_ALL signaling
TES
MY05A, HEXA, HEXB, MPV17, NTANl, AMN, DTNBPl, EPHB2,
WNT2, ADRB3, CD9, PDE6D, HNMT, TPP1, ATG7, CAMK2D,
GOTERM_
GO:0003008~system process 37 0,99999999 GAL3ST1, TES, GABRD, UNC119, CLN3, MOGAT2, PTGER3, 100 BP_ALL
MY06, SLC25A4, MAOA, NPR3, GPR98, P2RX4, LRAT, AAAS,
TSCl, FYN, CLN8, COMT1, APBB1, CLN6
MY05A, HEXA, HEXB, MPV17, NTANl, DTNBPl, EPHB2,
GOTERM_ GO:0050877~neurological WNT2, CD9, PDE6D, HNMT, TPP1, ATG7, GAL3ST1, TES,
31 1 100 BP_ALL system process GABRD, UNC119, CLN3, MY06, SLC25A4, MAOA, GPR98,
P2RX4, LRAT, AAAS, TSCl, FYN, APBB1, COMT1, CLN8, CLN6
MY05A, CLN3, UNC119, MY06, HEXA, HEXB, MPV17, NTANl,
GOTERM_
GO:0050890~cognition 18 1 DTNBPl, GPR98, EPHB2, LRAT, PDE6D, AAAS, FYN, CLN8, 100 BP_ALL
APBB1, CLN6
GOTERM_ GO:0007600~sensory MY05A, UNC119, MY06, HEXA, HEXB, MPV17, DTNBPl,
13 1 100 BP ALL perception GPR98, LRAT, PDE6D, FYN, CLN8, CLN6
Annotation Enrichment Score:
Cluster 57 0.6779583349658203 Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0007628~adult walking
4 0,1015709 HEXA, ATG7, HIPK2, CLN8 84,9070608 BP ALL behavior
GOTERM_ GO:0008344~adult
5 0,26062447 HEXA, ATG7, HIPK2, NTAN1, CLN8 99,51598237 BP ALL locomotory behavior
GOTERM_
GO:0030534~adult behavior 6 0,34941418 SLC1A2, HEXA, ATG7, HIPK2, NTAN1, CLN8 99,94942204 BP ALL
Annotation Enrichment Score:
Cluster 58 0.6559157518327583
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0030282~bone
3 0,11418496 BMP2, KLF10, GPN B 88,24125646 BP ALL mineralization
GOTER _ GO:0001649~osteoblast
5 0,13262376 BMP2, UBD, GPNMB, IGFBP3, BMP6 91,88896076 BP ALL differentiation
GOTER _ GO:0031214~biomineral
4 0,17922287 BMP2, ENPP1, KLF10, GPNMB 96,940304 BP ALL formation
GOTERM_ GO:0060348~bone
8 0,22476598 BMP2, INSIG2, KLF10, UBD, ACP5, GPNMB, IGFBP3, BMP6 98,8831955 BP ALL development
GOTERM_ GO:0001501~skeletal system SGPL1, BMP2, KLF10, HEXA, TGFBR2, HEXB, ACP5, GAS1,
14 0,4155068 99,99236907 BP ALL development INSIG2, UBD, GPNMB, IGFBP3, PLEKHA1, BMP6
GOTER _
GO:0001503~ossification 6 0,45769173 BMP2, KLF10, UBD, GPNMB, IGFBP3, BMP6 99,99796664 BP ALL
Annotation Enrichment Score:
Cluster 59 0.6437862168048161
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0008361~regulation of RTN4, WDTC1, TSC1, LOC640611, ZMAT3, MAPT, CD81,
9 0,08297723 78,33120044 BP ALL cell size LOC100047575, CDK4, APBB1, CLN8
GOTER _ GO:0001558~regulation of
8 0,09049922 RTN4, ZMAT3, MAPT, CD81, IGFBP3, APBB1, TTL, CYR61 81,26371453 BP ALL cell growth
GOTERM_ GO:0032535~regulation of RTN4, WDTC1, LIMA1, TSC1, LOC640611, ZMAT3, MAPT,
10 0,23296893 99,07441752 BP ALL cellular component size CD81, LOC100047575, CDK4, APBB1, CLN8
GOTER _ GO:0045926~negative
5 0,34606101 RTN4, ADRB3, ATXN2, ZMAT3, APBB1 99,94461684 BP ALL regulation of growth
GOTERM_ GO:0045792~negative
4 0,38336914 RTN4, TSC1, ZMAT3, APBB1 99,98036761 BP ALL regulation of cell size
GOTERM_ GO:0030308~negative
3 0,59103215 RTN4, ZMAT3, APBB1 99,99998605 BP ALL regulation of cell growth
Annotation Enrichment Score:
Cluster 60 0.6410194181675531
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0031399~regulation of ATG10, BMP2, ZEB2, KITL, PIAS3, ATG7, JUN, BAX, CD81, HBB-
12 0,08615182 79,61804781 BP ALL protein modification process Bl, HBB-B2, IGFBP3, FGD4
BMP2, TGFBR2, TRIB3, PRDX2, ZEB2, KIT, RBI, IRS1, KITL,
GOTERM_ GO:0042325~regulation of
18 0,10215199 CD74, CARD10, TSC1, BAX, JUN, CD81, HBB-Bl, HBB-B2, 85,07848004 BP_ALL phosphorylation
IGFBP3, FGD4
GO:0032270~positive
GOTERM_ BMP2, ATG10, LOC640611, PIAS3, ATG7, CD81, CDK4, KITL,
regulation of cellular protein 8 0,12558611 90,64516954 BP ALL CLN6
metabolic process
GO:0032268~regulation of CLN3, EIF4E3, ATG10, BMP2, CPEB2, LOC640611, ZEB2, CDK4,
GOTERM_
cellular protein metabolic 17 0,12895423 KITL, PIAS3, BAX, ATG7, JUN, CD81, HBB-Bl, HBB-B2, IGFBP3, 91,26132683 BP_ALL
process FGD4, CLN6
BMP2, TGFBR2, TRIB3, PRDX2, ZEB2, KIT, RBI, IRS1, KITL,
GOTERM_ GO:0019220~regulation of
18 0,13148283 CD74, CARD10, TSC1, BAX, JUN, CD81, HBB-Bl, HBB-B2, 91,69852373 BP_ALL phosphate metabolic process
IGFBP3, FGD4
GO:0051174~regulation of BMP2, TGFBR2, TRIB3, PRDX2, ZEB2, KIT, RBI, IRS1, KITL,
GOTERM_
phosphorus metabolic 18 0,13148283 CD74, CARD10, TSC1, BAX, JUN, CD81, HBB-Bl, HBB-B2, 91,69852373 BP ALL
process IGFBP3, FGD4
GO:0001932~regulation of
GOTER _ BMP2, BAX, JUN, CD81, ZEB2, HBB-Bl, HBB-B2, IGFBP3, KITL,
protein amino acid 9 0,13469017 92,22342396 BP_ALL FGD4
phosphorylation
GO:0051247~positive
GOTERM_ BMP2, ATGIO, LOC640611, PIAS3, ATG7, CD81, CDK4, KITL,
regulation of protein 8 0,17204052 96,43154207 BP_ALL CLN6
metabolic process GO:0031401~positive
GOTERM_
regulation of protein 6 0,22756465 BIV1P2, ATG10, PIAS3, ATG7, CD81, KITL 98,95227475 BP_ALL
modification process
CLN3, EIF4E3, ATGIO, BMP2, CPEB2, LOC640611, ZEB2, CDK4,
GOTERM_ GO:0051246~regulation of
18 0,30202594 KITL, PIAS3, BAX, ATG7, JUN, CD81, HBB-Bl, HBB-B2, IGFBP3, 99,8249992 BP_ALL protein metabolic process
UBE2E2, FGD4, CLN6
GO:0001934~positive
GOTERM_
regulation of protein amino 3 0,68605328 BMP2, CD81, KITL 99,99999987 BP_ALL
acid phosphorylation
GOTERM_ GO:0042327~positive
3 0,72210179 BMP2, CD81, KITL 99,99999998 BP ALL regulation of phosphorylation
GO:00l0562~positive
GOTERM_
regulation of phosphorus 3 0,73877944 BMP2, CD81, KITL 99,99999999 BP_ALL
metabolic process
GO:0045937~positive
GOTERM_
regulation of phosphate 3 0,73877944 BIVIP2, CD81, KITL 99,99999999 BP ALL
metabolic process
Annotation Enrichment Score-.
Cluster 61 0.6302733416137303
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0021537~telencephalon
7 0,08036983 SLC1A2, TSC1, BAX, ATG7, ZEB2, ID4, RARB 77,2173302 BP ALL development
GOTERM_ GO:0021761~limbic system
4 0,15846623 TSC1, BAX, ZEB2, ID4 95,24483273 BP ALL development
GOTERM_ GO:0021S43~pallium
5 0,18047397 TSC1, BAX, ATG7, ZEB2, ID4 97,02160547 BP ALL development
GOTERM_ GO:0030900~forebrain HHEX, NOTCHl, SLC1A2, TSC1, FYN, BAX, ATG7, ZEB2, ID4,
10 0,26567887 99,5711878 BP ALL development RARB
GOTERM_ GO:0021766~hippocampus
3 0,26578565 TSC1, ZEB2, ID4 99,5722873 BP ALL development
GOTERM_ GO:0007420~brain TGFBR2, ZEB2, GASl, WNT2, HHEX, SLC1A2, NOTCHl, TSC1,
15 0,32080529 99,89187625 BP ALL development FYN, BAX, MTPN, ATG7, ID4, RARB, TES
GOTERM_ GO:0007417~central nervous TGFBR2, ZEB2, GASl, EPHB2, WNT2, HHEX, SLC1A2, NOTCHl,
18 0,37699482 99,97645895 BP ALL system development TSC1, FYN, BAX, MTPN, ATG7, ARSA, ID4, RARB, CLN8, TES
GOTERM^ GO:0021987~cerebral cortex
3 0,46227825 TSC1, BAX, ATG7 99,99824978 BP ALL development
Annotation Enrichment Score:
Cluster 62 0.6023397664861309
Gene
Category Term PValue Genes FDR
Count
GO:0060742~epithelial cell
GOTERM_
differentiation involved in 4 0,01523175 AR, NOTCHl, PSAP, FOXAl, LOC100047556 23,73682363 BP_ALL
prostate gland development
GOTERM_ GO:0048608~reproductive TCF21, AR, NOTCHl, PSAP, BAX, FOXAl, BIK, LOC100047556,
9 0,17815814 96,86946887 BP ALL structure development F0XO3, KDR
GOTERM_ GO:0030850~prostate gland
4 0,22266788 AR, NOTCHl, PSAP, FOXAl, LOC100047556 98,82861407 BP ALL development
GOTERM_ GO:0030855~epithelial cell TCF21, AR, NOTCHl, PSAP, JUN, FOXAl, PPARG,
8 0,256223 99,46251176 BP ALL differentiation LOC100047556, KDR
GOTER _ GO:0060740~prostate gland
3 0,29722846 AR, NOTCHl, FOXAl, LOC100047556 99,80250301 BP ALL epithelium morphogenesis
GOTERM_ GO:0060S12~prostate gland
3 0,31288107 AR, NOTCHl, FOXAl, LOC100047556 99,8673038 BP ALL morphogenesis
GOTERM_ GO:0021700~developmental
6 0,41635134 MY05A, REC8, NOTCHl, FOXAl, LOC100047556, F0XO3, KDR 99,99256141 BP ALL maturation
GOTERM_ GO:0022612~gland
5 0,46927709 AR, NOTCHl, FOXAl, TGFBR2, LOC100047556, PLXND1 99,99861119 BP ALL morphogenesis
GOTERM_ GO:0003006~reproductive AR, PSAP, FOXAl, KIT, F0XO3, KITL, KDR, TCF21, NOTCHl,
12 0,54954673 99,99992321 BP ALL developmental process REC8, BAX, BIK, LOC100047556
GOTERM_
GO:0048469~cell maturation 4 0,61292524 REC8, FOXAl, LOC100047556, FOX03, KDR 99,99999472 BP ALL
Annotation Enrichment Score:
Cluster 63 0.552053425924597
Gene
Category Term PValue Genes FDR
Count
RTN4, JUB, EGFL7, RAB3D, BCAR1, RHOQ, MFGE8, PNPLA2,
GOTERM_ GO:0032879~regulation of
23 0,12992958 IRS1, ADA, CPT1A, APOA4, IGHG, SLC1A2, CD36, CAPN10, 91,43247776 BP ALL localization
FCGR2B, SORBS1, BAX, RRAS2, TEK, STMN1, TRIP6 GOTERM_ GO:0051050~positive
8 0,3156392 IGHG, SLC1A2, CAPNIO, SORBSl, FCGR2B, BAX, MFGE8, TRIP6 99,87639971 BP ALL regulation of transport
GOTERM_ GO:0051049~regulation of RAB3D, RHOQ, MFGE8, CPT1A, ADA, APOA4, IGHG, SLC1A2,
13 0,53819634 99,99988084 BP ALL transport CAPNIO, FCGR2B, SORBSl, BAX, TRIP6
Annotation Enrichment Score:
Cluster 64 0.5382149728263187
Gene
Category Term PValue Genes FDR
Count
GO:0030111~regulation of
GOTER _
Wnt receptor signaling 5 0,07882663 HHEX, ZEB2, SOX17, TAX1BP3, LRP4 76,53286503 BP_ALL
pathway
GO:003O178~negative
GOTERM_
regulation of Wnt receptor 3 0,29722846 S0X17, TAX1BP3, LRP4 99,80250301 BP ALL
signaling pathway
GO:0010648~negative
GOTERM_ CLN3, HHEX, RGS3, PRDX2, GAS1, SOX17, TAX1BP3, RGS16,
regulation of cell 9 0,51950861 99,99975996 BP_ALL LRP4
communication
GO:0009968~negative
GOTERM_
regulation of signal 8 0,57780859 HHEX, RGS3, PRDX2, GAS1, SOX17, TAX1BP3, RGS16, LRP4 99,99997554 BP_ALL
transduction
Annotation Enrichment Score:
Cluster 65 0.533O195974828963
Gene
Category Term PValue Genes FDR
Count
Y05A, SGPLl, JUB, FUT8, ENPP2, BCARl, ZEB2, KIT, CCL5,
GOTERM_
GO:0040011~locomotion 20 0,18996073 KITL, KDR, WNT2, CCL25, FYN, BAX, CKLF, APBB1, CYR61, 97,57501856 BP_ALL
CLN6, TES
GOTERM_ JUB, SGPLl, FUT8, BCARl, ZEB2, KIT, KITL, KDR, WNT2, CCL25,
GO:0016477~cell migration 14 0,20698085 98,33317373 BP ALL FYN, BAX, APBB1, TES
GOTER _ SGPLl, JUB, FUT8, BCARl, ZEB2, GAS1, KIT, KITL, EPHB2, KDR,
GO:0006928~cell motion 19 0,27759458 99,67875934 BP ALL WNT2, CCL25, CD9, EPHA7, ANK3, FYN, BAX, APBB1, TES
GOTERM_ GO:0001764~neuron
5 0,33646429 WNT2, FYN, BAX, APBB1, TES 99,92837251 BP ALL migration
GOTERM_ JUB, SGPLl, FUT8, BCARl, ZEB2, KIT, KITL, KDR, WNT2, CCL25,
GO:0048870~cell motility 14 0,41540262 99,99234502 BP ALL FYN, BAX, APBB1, TES
GOTER _ GO:0051674~localization of JUB, SGPLl, FUT8, BCARl, ZEB2, KIT, KITL, KDR, WNT2, CCL25,
14 0,41540262 99,99234502 BP ALL cell FYN, BAX, APBB1, TES
Annotation Enrichment Score:
Cluster 66 0.5303427991202295
Gene
Category Term PValue Genes FDR
Count
GO:0032102~negative
GOTERM_
regulation of response to 4 0,18986567 CLN3, PPARA, FCGR2B, ADA 97,56998964 BP_ALL
external stimulus
GOTERM_ GO:0032101~regulation of
7 0,26205335 IGHG, CLN3, PPARA, FCGR2B, GPX4, TGFBR2, ADA 99,53223321 BP ALL response to external stimulus
GO:0048585~negative
GOTERM_
regulation of response to 4 0,51538935 CLN3, PPARA, FCGR2B, ADA 99,99972092 BP_ALL
stimulus
Annotation Enrichment Score:
Cluster 67 0.5109221561820045
Gene
Category Term PValue Genes FDR
Count
MY05A, CLN3, PTGER3, FTL1, FTL2, SMAD7, HEXA, HEXB,
GOTERM_ LOC434624, ATP6V0C-PS2, CSRP3, KDR, ATP6V0C, P2RX4,
GO:0050801~ion homeostasis 20 0,03951362 50,92178392 BP_ALL CD9, TSC1, FYN, BAX, ASNA1, SLC4A4, NDUFS1, GAL3ST1,
CLN6
GOTERM_ GO:0055080~cation CLN3, PTGER3, FTL1, FTL2, LOC434624, HEXB, ATP6V0C-PS2,
11 0,24246044 99,2570744 BP ALL homeostasis CSRP3, KDR, ATP6V0C, BAX, SLC4A4, ASNA1, CLN6
GOTERM_ GO:0055065~metal ion
7 0,28362391 CLN3, PTGER3, BAX, HEXB, ASNA1, CSRP3, KDR 99,72294301 BP ALL homeostasis
GOTERM_ GO:0030003~cellular cation ATP6V0C, CLN3, FTLl, PTGER3, FTL2, BAX, HEXB, LOC434624,
9 0,30440304 99,83522822 BP ALL homeostasis ATP6VOC-PS2, ASNA1, CSRP3, CLN6
GOTERM_ GO:0055074~calcium ion
6 0,36616113 CLN3, PTGER3, BAX, HEXB, CSRP3, KDR 99,9680839 BP ALL homeostasis
GOTERM_ GO:0006875~cellular metal
6 0,40801325 CLN3, PTGER3, BAX, HEXB, ASNA1, CSRP3 99,99044453 BP ALL ion homeostasis GOTERM_ GO:0006874~cellular calcium
5 0,53218169 CLN3, PTGER3, BAX, HEXB, CSRP3 99,99985026 BP ALL ion homeostasis
GOTERM_ GO:0055066~di-, tri-valent CLN3, FTLl, PTGER3, FTL2, BAX, HEXB, LOC434624, CSRP3,
7 0,57636738 99,99997402 BP ALL inorganic cation homeostasis KDR
GO:0030005~cellular di-, tri-
GOTER _
valent inorganic cation 6 0,6652965 CLN3, FTLl, PTGER3, FTL2, BAX, HEXB, LOC434624, CSRP3 99,99999959 BP ALL
homeostasis
Annotation Enrichment Score:
Cluster 68 0.5091056838197924
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0001822~kidney
9 0,07957937 SGPLl, TCF21, BMP2, KIF3A, TSCl, BAX, RARB, ANXA4, LRP4 76,86911833 BP_ALL development
GOTER _ GO:0001657~ureteric bud
3 0,52963898 TCF21, BMP2, RARB 99,99983522 BP_ALL development
GOTER _ GO:0001656~metanephros
3 0,70453492 TCF21, BMP2, RARB 99,99999996 BP_ALL development
Annotation Enrichment Score:
Cluster 69 0.5079774651165372
Gene
Category Term PValue Genes FDR
Count
GOTER _
GO:0042311~vasodilation 4 0,1015709 WNT2, ADRB3, P2RX4, TES 84,9070608 BP ALL
GOTER _ GO:0046777~protein amino
5 0,2982494 WNT2, FYN, CAMK2D, KIT, TES 99,80750748 BP ALL acid autophosphorylation
GOTERM_ GO:0035150~regulation of
4 0,32563927 WNT2, ADRB3, P2RX4, TES 99,90468614 BP ALL tube size
GOTERM_ GO:0050880~regulation of
4 0,32563927 WNT2, ADRB3, P2RX4, TES 99,90468614 BP ALL blood vessel size
GOTERM_ GO:0003018~vascular process
4 0,34880463 WNT2, ADRB3, P2RX4, TES 99,94857886 BP_ALL in circulatory system
GOTERM_ GO:0008015~blood
6 0,49816883 WNT2, ADRB3, P2RX4, CAMK2D, NPR3, TES 99,99948304 BP ALL circulation
GOTERM_ GO:0003013~circulatory
6 0,49816883 WNT2, ADRB3, P2RX4, CAMK2D, NPR3, TES 99,99948304 BP_ALL system process
Annotation Enrichment Score:
Cluster 70 0.5075647142477299
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0007626~locomotory MY05A, MY06, ENPP2, HEXA, HEXB, NTANl, KIT, CCL5,
15 0,12912903 91,29223534 BP ALL behavior CCL25, ATG7, CKLF, HIPK2, CLN8, CLN6, CYR61
GOTERM_
GO:0042330~taxis 6 0,48210428 CCL25, ENPP2, CKLF, KIT, CCL5, CYR61 99,99909832 BP ALL
GOTER _
GOBOOegSS^chemotaxis 6 0,48210428 CCL25, ENPP2, CKLF, KIT, CCL5, CYR61 99,99909832 BP ALL
Annotation Enrichment Score:
Cluster 71 0.5072500935060863
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0042157~lipoprotein
6 0,2122968 APOA4, ATG10, CD36, ATG7, PIGQ, PIGP 98,51980125 BP ALL metabolic process
GOTERM_ GO:0006497~protein amino
4 0,34880463 ATG10, ATG7, PIGQ, PIGP 99,94857886 BP ALL acid lipidation
GOTERM_ GO:0042158~lipoprotein
4 0,40618514 ATG10, ATG7, PIGQ, PIGP 99,98990996 BP ALL biosynthetic process
Annotation Enrichment Score:
Cluster 72 0.48760872645412456
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0045761~regulation of
5 0,24217159 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,25205745 BP ALL adenylate cyclase activity
GOTER _ GO:0007190~activation of
4 0,2451167 ADRB3, ADCY9, ADCY6, CALCRL 99,30174653 BP ALL adenylate cyclase activity
GOTERM_ GO:0051349~positive
4 0,25647289 ADRB3, ADCY9, ADCY6, CALCRL 99,46569096 BP ALL regulation of lyase activity
GOTERM_ GO:0031281~positive
4 0,25647289 ADRB3, ADCY9, ADCY6, CALCRL 99,46569096 BP ALL regulation of cyclase activity GO:0045762~positive
GOTERM_
regulation of adenylate 4 0,25647289 ADRB3, ADCY9, ADCY6, CALCRL 99,46569096 BP_ALL
cyclase activity
GOTER _ GO:0031279~regulation of
5 0,26062447 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,51598237 BP_ALL cyclase activity
GOTER _ GO:0051339~regulation of
5 0,26062447 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,51598237 BP ALL lyase activity
GOTERM_ GO:0030817~regulation of
5 0,28877094 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,75606052 BP ALL cAMP biosynthetic process
GOTERM_ GO:0030814~regulation of
5 0,30776456 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,84873441 BP ALL cAMP metabolic process
GO:0030802~regulation of
GOTERM_
cyclic nucleotide biosynthetic S 0,33646429 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,92837251 BP_ALL
process
GO:0030808~regulation of
GOTER _
nucleotide biosynthetic 5 0,33646429 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,92837251 BP_ALL
process
GO:0030799~regulation of
GOTERM_
cyclic nucleotide metabolic 5 0,36526299 ADRB3, ADCY9, ADCY6, CALCRL, NPR3 99,96727598 BP_ALL
process
GO:0019932~second-
GOTER _
messenger-mediated 7 0,37277785 ADRB3, PIK3C2G, PTGER3, PI4KA, CALCRL, NPR3, RCAN2 99,97348148 BP_ALL
signaling
GOTERM_ GO:0006140~regulation of
5 0,38443779 ADRB3, ADCY9, ADCY6, CALCRL, IMPR3 99,9809597 BP_ALL nucleotide metabolic process
GO:0007188~G-protein
GOTER _
signaling, coupled to cAMP 4 0,40618514 ADRB3, PTGER3, CALCRL, NPR3 99,98990996 BP_ALL
nucleotide second messenger
GO:0007187~G-protein
GOTER _
signaling, coupled to cyclic 4 0,46198275 ADRB3, PTGER3, CALCRL, NPR3 99,99823272 BP_ALL
nucleotide second messenger
GOTERM_ GO:0019933~cAMP-mediated
4 0,47287693 ADRB3, PTGER3, CALCRL, NPR3 99,99876843 BP ALL signaling
GOTER _ GO:0019935~cyclic-
4 0,52572935 ADRB3, PTGER3, CALCRL, NPR3 99,99980929 BP ALL nucleotide-mediated signaling
Annotation Enrichment Score:
Cluster 73 0.4850549495316308
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009991~response to CLN3, PPARA, G6PC, SLC1A2, ACADS, ATG7, TEK, TGFBR2,
9 0,19387919 97,77398144 BP_ALL extracellular stimulus ARSA
GOTERM_ GO:0031667~response to
8 0,2065816 CLN3, PPARA, G6PC, ACADS, ATG7, TEK, TGFBR2, ARSA 98,31829601 BP ALL nutrient levels
GOTERM_ GO:0042594~response to
3 0,34393386 CLN3, ACADS, ATG7 99,9413487 BP ALL starvation
GOTERM_ GO:0007584~response to
3 0,83307179 TEK, TGFBR2, ARSA 100 BP ALL nutrient
Annotation Enrichment Score:
Cluster 74 0.47749879451188615
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0014031~mesenchymal
4 0,31404946 BMP2, NOTCH1, ZEB2, KITL 99,8712315 BP ALL cell development
GOTERM_ GO:0048762~mesenchymal
4 0,33722776 BMP2, NOTCH1, ZEB2, KITL 99,92981365 BP ALL cell differentiation
GOTERM_ GO:0060485~mesenchyme
4 0,34880463 BMP2, NOTCH1, ZEB2, KITL 99,94857886 BP ALL development
Annotation Enrichment Score:
Cluster 75 0.4652199806423088
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0060021~palate
5 0,05705308 SGPLl, INSIG2, TGFBR2, GASl, PLEKHA1 64,55281463 BP_ALL development
GOTERM_ GO:0001501~skeletal system SGPLl, B P2, KLF10, HEXA, TGFBR2, HEXB, ACP5, GASl,
14 0,4155068 99,99236907 BP_ALL development INSIG2, UBD, GPN B, IGFBP3, PLEKHA1, BMP6
GOTERM_ GO:0048705~skeletal system
6 0,63896141 SGPLl, INSIG2, TGFBR2, ACP5, GASl, PLEKHA1 99,99999846 BP ALL morphogenesis
GOTERM_ GO:0048562~embryonic
5 0,90946972 MY06, INSIG2, TGFBR2, GASl, RARB 100 BP ALL organ morphogenesis Annotation Enrichment Score:
Cluster 76 0.46068687149661297
Gene
Category Term PValue Genes FOR
Count
GOTERM_ GO:0006911~phagocytosis,
3 0,12824792 IGHG, FCGR2B, MFGE8 91,13537877 BP_ALL engulfment
GOTERM_ GO:0050766~positive
3 0,25004789 IGHG, FCGR2B, MFGE8 99,37803917 BP ALL regulation of phagocytosis
GOTERM_ GO:0050764~regulation of
3 0,28152163 IGHG, FCGR2B, MFGE8 99,70823264 BP_ALL phagocytosis
GOTERM_ GO:0051050~positive
8 0,3156392 IGHG, SLC1A2, CAPNIO, SORBSl, FCGR2B, BAX, MFGE8, TRIP6 99,87639971 BP ALL regulation of transport
GOTERM_
GO:0006909~phagocytosis 4 0,33722776 IGHG, CD36, FCGR2B, MFGE8 99,92981365 BP ALL
GO:0051130~positive
GOTERM_
regulation of cellular 7 0,40290135 WNT2, IGHG, SORBSl, FCGR2B, MAPT, MFGE8, TES 99,98887817 BP_ALL
component organization
GOTERM_ GO:0045807~positive
3 0,41924194 IGHG, FCGR2B, MFGE8 99,99318567 BP_ALL regulation of endocytosis
GOTERM_ GO:0030100~regulation of
3 0,64625683 IGHG, FCGR2B, MFGE8 99,99999892 BP ALL endocytosis
GOTERM_ GO:0060627~regulation of
4 0,68084776 IGHG, RAB3D, FCGR2B, MFGE8 99,99999982 BP ALL vesicle-mediated transport
Annotation Enrichment Score:
Cluster 77 0.4566837635542866
Gene
Category Term PValue Genes FDR
Count
GO:0001932~regulation of
GOTERM_ BMP2, BAX, JUN, CD81, ZEB2, HBB-Bl, HBB-B2, IGFBP3, KITL,
protein amino acid 9 0,13469017 92,22342396 BP_ALL FGD4
phosphorylation
GO:0001933~negative
GOTERM_
regulation of protein amino 3 0,25004789 BAX, JUN, IGFBP3 99,37803917 BP_ALL
acid phosphorylation
GOTERM_ GO:0042326~negative
3 0,31288107 BAX, JUN, IGFBP3 99,8673038 BP ALL regulation of phosphorylation
GO:0045936~negative
GOTERM_
regulation of phosphate 3 0,34393386 BAX, JUN, IGFBP3 99,9413487 BP_ALL
metabolic process
GO:0010563~negative
GOTERM_
regulation of phosphorus 3 0,34393386 BAX, JU , IGFBP3 99,9413487 BP_ALL
metabolic process
GO:0031400~negative
GOTERM_
regulation of protein 3 0,47620465 BAX, JUN, IGFBP3 99,99889871 BP_ALL
modification process
GO:0032269~negative
GOTERM_
regulation of cellular protein 4 0,58508393 CLN3, BAX, JUN, IGFBP3 99,999982 BP_ALL
metabolic process
GO:0051248~negative
GOTERM_
regulation of protein 4 0,63948425 CLN3, BAX, JUN, IGFBP3 99,99999849 BP_ALL
metabolic process
Annotation Enrichment Score:
Cluster 78 0.43836777431615254
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO.0043408~regulation of
8 0,09454437 SH3RF1, A0RB3, AR, PSAP, HIPK2, ZEB2, FGF21, FGD4 82,68167781 BP ALL MAPKKK cascade
GO:0043410~positive
GOTERM_
regulation of MAPKKK 4 0,31404946 ADRB3, AR, HIPK2, FGF21 99,8712315 BP_ALL
cascade
GO:0009967~positive
GOTERM_
regulation of signal 9 0,43142835 ADRB3, HHEX, AR, HIPK2, ZEB2, GASl, FGF21, KITL, ADA 99,99531378 BP_ALL
transduction
GOTERM_ GO:0010627~regulation of
8 0,4733008 SH3RF1, ADRB3, AR, PSAP, HIPK2, ZEB2, FGF21, FGD4 99,9987858 BP_ALL protein kinase cascade
GO:0010647~positive
GOTERM_
regulation of cell 9 0,5378202 ADRB3, HHEX, AR, HIPK2, ZEB2, GASl, FGF21, KITL, ADA 99,99987912 BP_ALL
communication GO:0010740~positive
GOTERM_
regulation of protein kinase 4 0,71858242 ADRB3, AR, HIPK2, FGF21 99,99999998 BP ALL
cascade
Annotation Enrichment Score:
Cluster 79 0.42679034717985126
Gene
Category Term PValue Genes FDR
Count
GO:0045582~positive
GOTERM_
regulation of T cell 5 0,04316976 TGFBR2, H2-AA, VNNl, CD74, ADA 54,11749686 BP ALL
differentiation
GOTERM_ GO:0045580~regulation of T
6 0,04925909 TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 59,00830319 BP ALL cell differentiation
GO:0045621~positive
GOTERM_
regulation of lymphocyte 5 0,05218842 TGFBR2, H2-AA, VNNl, CD74, ADA 61,18177563 BP_ALL
differentiation
GOTER _ GO:0045619~regulation of
6 0,09454233 TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 82,68098687 BP ALL lymphocyte differentiation
GOTERM_ GO:0002682~regulation of LM02, BCARl, KLF10, TGFBR2, PRDX2, FOX03, RBI, KITL,
17 0,2712354 99,62500212 BP ALL immune system process ADA, CD74, IGHG, FCGR2B, CD81, H2-AA, VNNl, CFD, TOB2
GOTERM_ GO:0050870~positive
5 0,2982494 TGFBR2, H2-AA, VNNl, CD74, ADA 99,80750748 BP ALL regulation of T cell activation
GO:0051251~positive
GOTERM_
regulation of lymphocyte 6 0,35778423 CD81, TGFBR2, H2-AA, VNNl, CD74, ADA 99,95975812 BP_ALL
activation
GOTERM_ GO:0051249~regulation of
8 0,3978818 FCGR2B, CD81, TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 99,98710675 BP ALL lymphocyte activation
GO:0002696~positive
GOTERM_
regulation of leukocyte 6 0,39965959 CD81, TGFBR2, H2-AA, VNNl, CD74, ADA 99,98776255 BP_ALL
activation
GOTERM_ GO:0050867~positive
6 0,41635134 CD81, TGFBR2, H2-AA, VNNl, CD74, ADA 99,99256141 BP ALL regulation of cell activation
GOTERM_ GO:0002252~immune
7 0,43292559 IGHG, IGH, FCGR2B, H2-AA, PRDX2, CFD, CD74 99,99552693 BP_ALL effector process
GOTERM_ GO:0002694~regulation of
8 0,46651754 FCGR2B, CD81, TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 99,99847803 BP ALL leukocyte activation
GOTERM_ GO:0050863~regulation of T
6 0,47400619 TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 99,99881419 BP ALL cell activation
GOTERM_ GO:0050865~regulation of
8 0,48006218 FCGR2B, CD81, TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 99,99903344 BP ALL cell activation
GO:0002683~negative
GOTER _
regulation of immune system 4 0,62192212 FCGR2B, PRDX2, CD74, ADA 99,99999651 BP_ALL
process
GO:0002684~positive
GOTERM_
regulation of immune system 9 0,63567225 IGHG, BCARl, CD81, TGFBR2, H2-AA, VNNl, CFD, CD74, ADA 99,99999819 BP_ALL
process
GOTERM_
GO:0042113~B cell activation 4 0,63948425 BAX, MS4A1, ADA, BLNK 99,99999849 BP ALL
GO:0051250~negative
GOTERM_
regulation of lymphocyte 3 0,64625683 FCGR2B, PRDX2, CD74 99,99999892 BP ALL
activation
GO:0002695~negative
GOTER _
regulation of leukocyte 3 0,65656615 FCGR2B, PRDX2, CD74 99,99999936 BP_ALL
activation
GOTERM_ GO:0050866~negative
3 0,65656615 FCGR2B, PRDX2, CD74 99,99999936 BP ALL regulation of cell activation
GOTER _ GO:0045321~leukocyte FCGR2B, FYN, BAX, TGFBR2, MS4A1, PRDX2, CD74, ADA,
9 0,70208823 99,99999995 BP ALL activation BLNK
GOTERM_ FCGR2B, FYN, BAX, TGFBR2, MS4A1, PRDX2, ENTPD2, CD74,
GO:0001775~cell activation 10 0,70660205 99,99999996 BP ALL ADA, BLNK
GOTERM_ GO:0046649~lymphocyte
7 0,81576403 FYN, BAX, S4A1, PRDX2, CD74, ADA, BLNK 100 BP ALL activation
GOTERM_ GO:0002521~leukocyte
5 0,85061365 BAX, TGFBR2, KIT, CD74, ADA 100 BP ALL differentiation
GOTERM_ GO:0030098~lymphocyte
3 0,9548519 BAX, CD74, ADA 100 BP ALL differentiation
Annotation Enrichment Score:
Cluster 80 0.41929589759423297
Gene
Category Term PValue Genes FDR
Count GOTERM_ GO:0006766~vitamin
6 0,16181831 NA PT, AKR1A4, PDXK, LRAT, RDH16, RETSAT 95,56836856 BP ALL metabolic process
GOTERM_ GO:0006776~vitamin A
3 0,29722846 LRAT, RDH16, RETSAT 99,80250301 BP ALL metabolic process
GOTERM_ GO:0019748~secondary
5 0,32687847 MYOSA, NAMPT, LRAT, RDH16, RETSAT 99,90773144 BP ALL metabolic process
GOTERM_ GO:0016101~diterpenoid
3 0,32845651 LRAT, RDH16, RETSAT 99,91147668 BP ALL metabolic process
GOTER _ GO:0001523~retinoid
3 0,32845651 LRAT, RDH16, RETSAT 99,91147668 BP ALL metabolic process
GOTERM_ GO:0006720~isoprenoid
4 0,33722776 LRAT, FDPS, RDH16, RETSAT 99,92981365 BP ALL metabolic process
GOTERM_ GO:0006721~terpenoid
3 0,34393386 LRAT, RDH16, RETSAT 99,9413487 BP_ALL metabolic process
GOTERM_ GO:0006775~fat-soluble
3 0,41924194 LRAT, RDH16, RETSAT 99,99318567 BP_ALL vitamin metabolic process
GOTERM_ GO:0010817~regulation of
6 0,62532499 Y05A, LRAT, FOXAl, LOC100047556, RDH16, IRSl, RETSAT 99,99999703 BP ALL hormone levels
GOTERM_ GO:0034754~cellular
3 0,64625683 LRAT, RDH16, RETSAT 99,99999892 BP ALL hormone metabolic process
GOTER _ GO:0042445~hormone
4 0,73267456 LRAT, FOXAl, LOC100047556, RDH16, RETSAT 99,99999999 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 81 0.406515855315568
Gene
Category Term PValue Genes FDR
Count
GOTERIVL GO:0018193~peptidyl-amino
8 0,28225751 PDK1, PDK2, P4HA2, RAB3D, FYN, PDK4, KIT, EPHB2 99,71346369 BP ALL acid modification
GOTERM_ GO:0018108~peptidyl-
3 0,46227825 FYN, KIT, EPHB2 99,99824978 BP ALL tyrosine phosphorylation
GOTERM_ GO:0018212~peptidyl-
3 0,46227825 FYN, KIT, EPHB2 99,99824978 BP ALL tyrosine modification
Annotation Enrichment Score:
Cluster 82 0.40573339726627033
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0019319~hexose
3 0,28152163 GPD2, G6PC, GNPDA1 99,70823264 BP ALL biosynthetic process
GOTERM_ GO:0046364~monosaccharide
3 0,37451988 GPD2, G6PC, GNPDA1 99,97475214 BP ALL biosynthetic process
GO:0034637~cellular
GOTERM_
carbohydrate biosynthetic 4 0,41750075 GPD2, G6PC, GNPDA1, GYG 99,99281584 BP_ALL
process
GOTERM_ GO:0016051~carbohydrate
5 0,46002947 GPD2, G6PC, GNPDA1, GYG, CHST14 99,99811595 BP ALL biosynthetic process
GOTERM_ GO:0046165~alcohol
3 0,46227825 GPD2, G6PC, GNPDA1 99,99824978 BP ALL biosynthetic process
Annotation Enrichment Score:
Cluster 83 0.4051077882625091
Gene
Category Term PValue Genes FDR
Count
PDXK, ADCY6, ATP6V1B2, ATP6V0C-PS2, ADA, ATP6V0B,
GOTERM_ GO:0046483~heterocycle
17 0,15030919 APRT, ATP6V0C, MTHFS, ATP6V1A, ALAS1, G6PC, ADCY9, 94,36196722 BP_ALL metabolic process
P4HA2, PTS, ENTPD2, NDUFS1, PRODH
GOTER _ GO:0015992~proton
5 0,17212664 ATP6V0C, ATP6V1A, NNT, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 96,4380893 BP ALL transport
GOTERM_ GO:0006818~hydrogen
5 0,18047397 ATP6V0C, ATP6V1A, NNT, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 97,02160547 BP ALL transport
GOTERM_ GO:0015986~ATP synthesis
4 0,20066415 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 98,0825616 BP ALL coupled proton transport
GO:0015985~energy coupled
GOTER _
proton transport, down 4 0,20066415 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 98,0825616 BP ALL
electrochemical gradient
GOTERM_ GO:0006119~oxidative ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B,
5 0,20627609 98,30682728 BP ALL phosphorylation NDUFS1
ENPP5, NAMPT, ADCY6, UPP2, ATP6V0C-PS2, ATP6V1B2,
GOTER _ GO:0006753~nucleoside
14 0,23624376 PRPSAPl, ADA, ATP6V0B, ATP6V0C, ATP6V1A, ADCY9, NT5C2, 99,14175837 BP_ALL phosphate metabolic process
ENTPD2, NDUFS1 ENPPS, NAMPT, ADCY6, UPP2, ATP6V0C-PS2, ATP6V1B2,
GOTERM_ GO:0009117~nucleotide
14 0,23624376 PRPSAPl, ADA, ATP6V0B, ATP6V0C, ATP6V1A, ADCY9, NT5C2, 99,14175837 BP_ALL metabolic process
ENTPD2, NDUFS1
GO:0055086~nucleobase, ENPP5, NAMPT, ADCY6, UPP2, ATP6V1B2, ATP6V0C-PS2,
GOTERM_
nucleoside and nucleotide 15 0,23768384 PRPSAPl, ADA, ATP6V0B, APRT, ATP6V0C, ATP6V1A, ADCY9, 99,16988359 BP_ALL
metabolic process NT5C2, ENTPD2, NDUFS1
GOTERM_ GO:0034220~ion
4 0,25647289 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 99,46569096 BP_ALL transmembrane transport
GO:0044271~nitrogen NAMPT, DDC, ADCY6, ATP6V1B2, ATP6V0C-PS2, PRPSAPl,
GOTERM_
compound biosynthetic 16 0,28379518 ADA, ATP6V0B, APRT, ATP6V0C, ADI1, ATP6V1A, P2RX4, 99,7241101 BP_ALL
process ALAS1, ADCY9, PTS, PRODH
GO:0034404~nucleobase,
GOTER _ ATP6V0C, NAMPT, ATP6V1A, ADCY9, ADCY6, ATP6V1B2,
nucleoside and nucleotide 10 0,33468008 99,92489496 BP_ALL ATP6V0C-PS2, PRPSAPl, ADA, ATP6V0B, APRT
biosynthetic process
GO:0034654~nucleobase,
GOTERM_ nucleoside, nucleotide and ATP6V0C, NAMPT, ATP6V1A, ADCY9, ADCY6, ATP6V1B2,
10 0,33468008 99,92489496 BP_ALL nucleic acid biosynthetic ATP6V0C-PS2, PRPSAPl, ADA, ATP6V0B, APRT
process
GOTER _ GO:0006163~purine ATP6V0C, ATP6V1A, ADCY9, ADCY6, ATP6V1B2, ATP6V0C-
9 0,35468623 99,95618974 BP ALL nucleotide metabolic process PS2, ENTPD2, ADA, ATP6V0B, NDUFS1
GO:0009150~purine
GOTERM_ ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ENTPD2, ADA,
ribonucleotide metabolic 7 0,38030861 99,97857434 BP_ALL ATP6V0B, NDUFS1
process
GOTERM_ GO:0009259~ribonucleotide ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ENTPD2, ADA,
7 0,42543798 99,99436126 BP ALL metabolic process ATP6V0B, NDUFS1
GOTERM_ GO:0009165~nucleotide ATP6V0C, NAMPT, ATP6V1A, ADCY9, ADCY6, ATP6V1B2,
9 0,44419421 99,99686158 BP ALL biosynthetic process ATP6V0C-PS2, PRPSAPl, ADA, ATP6V0B
GO:0009144~purine
GOTERM_ ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ADA,
nucleoside triphosphate 6 0,45769173 99,99796664 BP_ALL ATP6V0B, NDUFS1
metabolic process
GO:0006164~purine
GOTERM_ ATP6V0C, ATP6V1A, ADCY9, ADCY6, ATP6V1B2, ATP6V0C- nucleotide biosynthetic 7 0,51370107 99,99970325 BP_ALL PS2, ADA, ATP6V0B
process
GOTERM_ GO:0046034~ATP metabolic ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B,
5 0,52341374 99,99979217 BP ALL process NDUFS1
GO:0009141~nucleoside
GOTERM_ ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ADA,
triphosphate metabolic 6 0,52970286 99,99983562 BP_ALL ATP6V0B, NDUFS1
process
GO:0009124~nucleoside
GOTERM_
monophosphate biosynthetic 3 0,56721189 ADCY9, ADCY6, ADA 99,99996211 BP_ALL
process
GO:0009205~purine
GOTER _ ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B,
ribonucleoside triphosphate 5 0,615081 99,99999522 BP_ALL NDUFS1
metabolic process
GO:0009199~ribonucleoside
GOTERM_ ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B,
triphosphate metabolic 5 0,62285286 99,99999666 BP_ALL NDUFS1
process
GO:0009152~purine
GOTERM_
ribonucleotide biosynthetic 5 0,66019873 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ADA, ATP6V0B 99,99999947 BP_ALL
process
GOTERM_ GO:0006754~ATP
4 0,67286638 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 99,99999973 BP ALL biosynthetic process
GOTER _ GO:0009260~ribonucleotide
5 0,68821913 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ADA, ATP6V0B 99,99999988 BP ALL biosynthetic process
GO:0009123~nucleoside
GOTERM_
monophosphate metabolic 3 0,71343115 ADCY9, ADCY6, ADA 99,99999997 BP_ALL
process
GO:0009206~purine
GOTERM_
ribonucleoside triphosphate 4 0,752763 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 100 BP_ALL
biosynthetic process
GO:0009201~ribonucleoside
GOTERM_
triphosphate biosynthetic 4 0,752763 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 100 BP_ALL
process
GO:0009145~purine
GOTERM_
nucleoside triphosphate 4 0,75918397 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 100 BP_ALL
biosynthetic process
GO:0009142~nucleoside
GOTERM_
triphosphate biosynthetic 4 0,76546956 ATP6V0C, ATP6V1A, ATP6V1B2, ATP6V0C-PS2, ATP6V0B 100 BP_ALL
process
Annotation Enrichment Score:
Cluster 84 0.40069547078158185 Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0046394~carboxylic acid
8 0,37718404 ACSM3, MY05A, ADIl, AKR1A4, FADS2, ACACB, CD74, PRODH 99,97658486 BP ALL biosynthetic process
GOTERM_ GO:0016053~organic acid
8 0,37718404 ACSM3, MY05A, ADIl, AKR1A4, FADS2, ACACB, CD74, PRODH 99,97658486 BP ALL biosynthetic process
GOTERM_ GO:0006633~fatty acid
5 0,44137422 ACSM3, MY05A, FADS2, ACACB, CD74 99,99656826 BP ALL biosynthetic process
Annotation Enrichment Score:
Cluster 85 0.38665297240101726
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048592~eye
6 0,19005491 MFN2, BHLHE22, BAX, GAS1, RARB, EPHB2 97,57999138 BP ALL morphogenesis
GOTERM_ GO:0048593~camera-type
4 0,32563927 MFN2, BHLHE22, BAX, EPHB2 99,90468614 BP ALL eye morphogenesis
GO:0060041~retina
GOTERM_
development in camera-type 3 0,38959561 BHLHE22, BAX, CLN8 99,98358811 BP_ALL
eye
GOTERM_ GO:0001654~eye
8 0,48680001 MFN2, MEIS2, BHLHE22, BAX, GAS1, RARB, CLN8, EPHB2 99,99923225 BP ALL development
GOTERM_ GO:0007423~sensory organ MFIN2, MY06, MEIS2, BHLHE22, INSIG2, BAX, GAS1, RARB,
11 0,63830322 99,99999841 BP ALL development CLN8, GPR98, EPHB2
GOTERM_ GO:0043010~camera-type
6 0,63896141 MFN2, BHLHE22, BAX, GAS1, CLN8, EPHB2 99,99999846 BP ALL eye development
Annotation Enrichment Score:
Cluster 86 0.36435061962684
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009100~glycoprotein CLN3, ST3GAL3, LARGE, FUT8, ST8SIA4, BACE1, CHST14,
9 0,27382603 99,64785273 BP ALL metabolic process ST8SIA3, ST6GALNAC2
GOTERM_ GO:0009101~glycoprotein ST3GAL3, LARGE, FUT8, ST8SIA4, CHST14, ST8SIA3,
7 0,36525182 99,96726582 BP ALL biosynthetic process ST6GALNAC2
GOTERM_
GO:0070085~glycosylation 5 0,53218169 ST3GAL3, FUT8, ST8SIA4, ST8SIA3, ST6GALNAC2 99,99985026 BP ALL
GOTERM_ GO:0006486~protein amino
5 0,53218169 ST3GAL3, FUT8, ST8SIA4, ST8SIA3, ST6GALNAC2 99,99985026 BP ALL acid glycosylation
GOTERM_ GO:0043413~biopolymer
5 0,53218169 ST3GAL3, FUT8, ST8SIA4, ST8SIA3, ST6GALNAC2 99,99985026 BP ALL glycosylation
Annotation Enrichment Score:
Cluster 87 0.3638819295446521
Gene
Category Term PValue Genes FDR
Count
BID, FA 176A, SGPL1, ZMAT3, CYCS, EGLN3, TRIB3, GAS2,
GOTERM_ GO:0012501~programmed
23 0,33660042 GAS1, KIT, DNASE1L3, KITL, CIDEC, PLEKHF1, CASP6, BAX, 99,92863148 BP_ALL cell death
BAG2, HIPK2, GATAD2A, APBB1, DEDD2, NDUFS1, PEG3
BID, FAM176A, SGPL1, ZMAT3, CYCS, EGLN3, TRIB3, GAS2,
GOTERM_ GAS1, KIT, DNASE1L3, KITL, CIDEC, PLEKHF1, CASP6, BAX,
GO:0008219~cell death 24 0,37193977 99,97284891 BP_ALL BAG2, HIPK2, GATAD2A, CLN8, APBB1, DEDD2, NDUFS1,
PEG3
BID, FAM176A, SGPL1, ZMAT3, CYCS, EGLN3, TRIB3, GAS2,
GOTERM_ GAS1, KIT, DNASE1L3, KITL, CIDEC, PLEKHF1, CASP6, BAX,
GO:0016265~death 24 0,41898346 99,99313193 BP_ALL BAG2, HIPK2, GATAD2A, CLN8, APBB1, DEDD2, NDUFS1,
PEG3
FAM176A, BID, SGPL1, ZMAT3, CYCS, EGLN3, TRIB3, GAS2,
GOTERM_
GO.000691S~apoptosis 19 0,66786417 DNASE1L3, CIDEC, PLEKHF1, CASP6, BAX, BAG2, HIPK2, 99,99999965 BP ALL APBB1, DEDD2, NDUFS1, PEG3
Annotation Enrichment Score:
Cluster 88 0.3614835881063023
Gene
Category Term PValue Genes FDR
Count
BCARl, ZMAT3, RHOQ, PRDX2, FOX03, PTTGl, OBFC2A, MIF,
GOTERM_ GO:0051716~cellular SLC1A2, PDE6D, SORBS1, RAD51L1, GPX4, GPX3, NSMCE2,
28 0,23727333 99,16195598 BP_ALL response to stimulus FGD4, CLN3, WDTC1, TOPBPl, IRS1, LPIN1, DCLRE1A,
CAPN10, NUPR1, BAX, HIPK2, DDB2, LOC100047575, APBB1
CLN3, ZMAT3, PRDX2, TOPBPl, F0XO3, PTTGl, OBFC2A, MIF,
GOTERM_ GO:0033554~cellular
19 0,42660923 DCLRE1A, NUPR1, RAD51L1, GPX4, BAX, GPX3, HIPK2, DDB2, 99,99456079 BP ALL response to stress
NSMCE2, APBB1, FGD4 GOTERM_ GO:0006974~response to ZMAT3, TOPBP1, FOX03, PTTG1, OBFC2A, MIF, DCLRE1A,
14 0,42823832 99,99482725 BP ALL DNA damage stimulus NUPR1, RAD51L1, BAX, HIPK2, DDB2, NSMCE2, APBB1
GOTERM_ DCLRE1A, RAD51L1, DDB2, NS CE2, TOPBP1, PTTGl,
GO:0006281~DNA repair 8 0,82622999 100 BP ALL OBFC2A, APBB1
Annotation Enrichment Score:
Cluster 89 0.3373241171806076
Gene
Category Term PValue Genes FDR
Count
FTLl, FTL2, SLC20A1, LOC434624, ATP6V0C-PS2, ATP6V1B2,
TPCN1, ATP6V0B, WNT2, ATP6V0C, SLC01A4, SLC1A2,
GOTERM_ KCNK5, CA K2D, SLC39A8, MCOLNl, AI317395, SLC4A4,
GO:0006811~ion transport 35 0,23801963 99,17631531 BP ALL SLC31A2, TES, GABRD, PTGER3, SLC25A4, SLC24A6, TCN2,
KCNK3, SLC01B2, P2RX4, ATP6V1A, NNT, SLC16A7, TSC1,
SLC6A8, TO M40L, KCTD17, 2010001E11RIK, SLC40A1, CLN8
FTLl, FTL2, LOC434624, ATP6V0C-PS2, ATP6V1B2, ATP6V0B,
TPCN1, ATP6V0C, KCNK5, SLC39A8, CAMK2D, MCOLNl,
GOTERM_
GO:0006812~cation transport 23 0,49481063 AI317395, SLC4A4, SLC31A2, SLC24A6, TCN2, KCNK3, P2RX4, 99,99941844 BP_ALL
ATP6V1A, NNT, TSC1, SLC6A8, KCTD17, 2010001E11RIK,
SLC40A1
SLC24A6, ATP6V1B2, ATP6V0C-PS2, ATP6V0B, KCNK3,
GOTERM_ GO:0015672~monovalent
14 0,50389895 ATP6V0C, ATP6V1A, NNT, TSC1, SLC6A8, KC K5, KCTD17, 99,99957791 BP_ALL inorganic cation transport
2010001E11RIK, AI317395, SLC4A4
GOTERM_ GO:0015674~di-, tri-valent P2RX4, FTLl, FTL2, LOC434624, CAMK2D, SLC24A6, MCOL l,
8 0,51348337 99,99970089 BP ALL inorganic cation transport TCN2, SLC40A1, TPCN1
FTLl, FTL2, LOC434624, SLC24A6, TCN2, TPCN1, KCNK3,
GOTER _ GO:0030001~metal ion P2RX4, TSC1, SLC6A8, KCNK5, CAMK2D, KCTD17, SLC39A8,
18 0,67523942 99,99999976 BP_ALL transport 2010001E11RIK, MCOLNl, SLC31A2, AI31739S, SLC4A4,
SLC40A1
Annotation Enrichment Score:
Cluster 90 0.31543773938953823
Gene
Category Term PValue Genes FDR
Count
ENPP1, ENPP2, BCAR1, ACP5, PRDX2, KIT, TLR5, CCL5, CD74,
ADA, MIF, APOA4, TCF21, CCL25, LOC641240, MS4A1, VNN1,
GOTERM_ GO:0002376~immune system HBB-Bl, HBB-B2, CFD, DEFBl, BLNK, SGPLl, IGH, RMCS2, IGJ,
39 0,20321542 98,18778265 BP_ALL process TGFBR2, H2-AB1, BPGM, RBI, RMCS5, KDR, HBA-Al, HBA-A2,
IGHG, CCNB2, FCGR2B, C920025E04RIK, FYN, BAX, H2-EB1,
H2-AA, GBP1
GOTERM_ GO:0048872~homeostasis of
7 0,33525299 HBA-Al, HBA-A2, LIPA, CCNB2, BAX, PRDX2, BPGM, RBI 99,92602858 BP ALL number of cells
GOTERM_ GO:0048534~hemopoietic or SGPLl, TGFBR2, PRDX2, BPGM, KIT, RBI, ADA, CD74, KDR,
14 0,39567458 99,98624636 BP ALL lymphoid organ development HBA-Al, HBA-A2, TCF21, CCNB2, BAX, HBB-Bl, HBB-B2
GOTER _ GO:0002520~immune system SGPLl, TGFBR2, PRDX2, BPGM, KIT, RBI, ADA, CD74, KDR,
14 0,47159587 99,99871451 BP ALL development HBA-Al, HBA-A2, TCF21, CCNB2, BAX, HBB-Bl, HBB-B2
GOTERM_ GO:0030099~myeloid cell
5 0,57476855 HBA-Al, HBA-A2, TGFBR2, BPGM, RBI, KIT 99,99997223 BP ALL differentiation
GOTERM_ GO:0030218~erythrocyte
3 0,60257097 HBA-Al, HBA-A2, BPGM, RBI 99,99999158 BP ALL differentiation
GOTERM_ SGPLl, TGFBR2, BPGM, KIT, RBI, ADA, CD74, KDR, HBA-Al,
GO:0030097~hemopoiesis 11 0,60860339 99,99999358 BP ALL HBA-A2, BAX, HBB-Bl, HBB-B2
GOTERM_ GO:0034101~erythrocyte
3 0,63570404 HBA-Al, HBA-A2, BPGM, RBI 99,99999819 BP_ALL homeostasis
GOTERM_ GO:0002521~leukocyte
5 0,85061365 BAX, TGFBR2, KIT, CD74, ADA 100 BP ALL differentiation
Annotation Enrichment Score:
Cluster 91 0.2974784000350781
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0021915~neural tube
6 0,26700705 NOTCH1, KIF3A, TSC1, GATAD2A, 2EB2, GAS1 99,58467642 BP ALL development
GOTERM_ GO:0060562~epithelial tube
7 0,32035833 TCF21, HHEX, AR, BMP2, TSC1, GATAD2A, ZEB2 99,89061316 BP ALL morphogenesis
GOTERM_
GO:0060606~tube closure 3 0,48990934 TSC1, GATAD2A, ZEB2 99,99931036 BP ALL
GOTER _ GO:0001843~neural tube
3 0,48990934 TSC1, GATAD2A, ZEB2 99,99931036 BP ALL closure
GOTER _ GO:0014020~primary neural
3 0,52963898 TSC1, GATAD2A, ZEB2 99,99983522 BP ALL tube formation
GOTERM_ GO:0001841~neural tube
3 0,63570404 TSC1, GATAD2A, ZEB2 99,99999819 BP ALL formation GOTERM_ GO:0016331~morphogenesis
4 0,63948425 HHEX, TSC1, GATAD2A, ZEB2 99,99999849 BP ALL of embryonic epithelium
GOTERM_ GO:0001838~embryonic
3 0,66663387 TSC1, GATAD2A, ZEB2 99,99999962 BP ALL epithelial tube formation
GOTERM_ GO:0035148~tube lumen
3 0,71343115 TSC1, GATAD2A, ZEB2 99,99999997 BP ALL formation
Annotation Enrichment Score:
Cluster 92 0.292185568612512
Gene
Category Term PValue Genes FDR
Count
GOTERM_
GO:0007127~meiosis 1 4 0,17922287 REC8, SYCE2, TOPBP1, PTTGl 96,940304 BP ALL
GOTERM_
GO:0007126~meiosis 4 0,71858242 REC8, SYCE2, TOPBP1, PTTGl
BP ALL 99,99999998
GOTERM_ GO:0051327~M phase of
4 0,71858242 REC8, SYCE2, TOPBP1, PTTGl
BP ALL 99,99999998 meiotic cell cycle
GOTERM_ GO:0051321~meiotic cell
4 0,73267456 REC8, SYCE2, TOPBP1, PTTGl 99,99999999 BP ALL cycle
Annotation Enrichment Score:
Cluster 93 0.2886119594268504
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048589~developmental MY05A, AR, NOTCH1, PSAP, MTPN, FOX03, GASl, TIMP3,
9 0,05815688 65,27828264 BP_ALL growth LRP4
GOTER _ GO:0001942~hair follicle
3 0,62490624 MY05A, NOTCH 1, LRP4 99,99999697 BP ALL development
GOTERM_ GO:0022404~molting cycle
3 0,62490624 MY05A, NOTCH 1, LRP4
BP ALL 99,99999697 process
GOTERM_ GO:0022405~hair cycle
3 0,62490624 MY05A, NOTCH1, LRP4 99,99999697 BP ALL process
GOTERM_
GO:0042633~hair cycle 3 0,64625683 MY05A, NOTCH1, LRP4 99,99999892 BP ALL
GOTERM_
GO:0042303~molting cycle 3 0,64625683 MY05A, NOTCH 1, LRP4 99,99999892 BP ALL
GOTERM_ GO:0008544~epidermis
4 0,89948264 MY05A, PPARA, NOTCH 1, LRP4 100 BP ALL development
GOTERM_ GO:0007398~ectoderm
4 0,92099133 MY05A, PPARA, NOTCH 1, LRP4 100 BP ALL development
Annotation Enrichment Score:
Cluster 94 0.28685070949061475
Gene
Category Term PValue Genes FDR
Count
PPARA, BCARl, PPARG, ZEB2, FOX03, WNT2, CASP6,
SMARCD3, MAPT, SDPR, KIFAP3, ATG7, GPX4, VIMN1, RARB,
CALCRL, CYR61, AR, CYCS, MFGE8, PNPLA2, FGF21, RBI,
CDK4, IRS1, PPARGC1A, PPARGC1B, VEGFB, IGHG, HHEX,
GOTERM_ GO:0048522~positive CD36, CAPN10, PIAS3, JUN, RRAS2, CD81, HIPK2, H2-AA,
74 0,00811666 13,40094421 BP_ALL regulation of cellular process STMN1, CLN6, BID, ATG10, LOC640611, CYTH3, KIT, CD74,
ADA, EPHB2, TCF21, ADRB3, MEIS2, SORBSl, SMOCl, TES,
BMP2, KLFIO, FOXAl, TGFBR2, GASl, KITL, CIDEC, KDR,
PLEKHF1, EPHA7, NOTCH 1, FCGR2B, NUPR1, BAX, CENPV,
ID4, BIK, LOC100047556, NFIC, TRIP6, IGFBP3, APBB1
PPARA, BCARl, PPARG, ZEB2, FOX03, WNT2, CASP6, SLC1A2,
SMARCD3, MAPT, SDPR, KIFAP3, ATG7, GPX4, VNNl, RARB,
CALCRL, CFD, CYR61, AR, CYCS, MFGE8, PNPLA2, FGF21, RBI,
CDK4, I S1, PPARGC1A, PPARGC1B, VEGFB, IGHG, HHEX,
GO:0048518~positive CD36, CAPN10, PIAS3, JUN, RRAS2, CD81, HIPK2, H2-AA,
GOTERM_
regulation of biological 79 0,02304986 STMN1, CLN6, BID, ATG10, RAG1AP1, LOC640611, CYTH3, 33,74770623 BP ALL
process KIT, SEC14L2, CD74, ADA, EPHB2, TCF21, ADRB3, MEIS2,
SORBSl, SMOCl, TES, BMP2, KLFIO, FOXAl, TGFBR2, GASl,
KITL, CIDEC, KDR, PLEKHF1, EPHA7, NOTCHl, FCGR2B,
NUPR1, BAX, CENPV, BIK, ID4, LOC100047556, NFIC, TRIP6,
IGFBP3, APBB1, TOB2
PPARA, ATG10, RAG1AP1, LOC640611, PPARG, KIT, FOX03,
GO:0009893~positive SEC14L2, TCF21, ADRB3, MEIS2, SORBSl, SMARCD3, GPX4,
GOTERM_
regulation of metabolic 34 0,2174381 ATG7, SDPR, RARB, BMP2, AR, FOXAl, PNPLA2, RBI, CDK4, 98,68140359 BP_ALL
process KITL, IRS1, PPARGC1A, PPARGC1B, NOTCHl, PIAS3, JUN,
HIPK2, CD81, LOC100047556, NFIC, APBB1, CLN6 PPARA, ATG10, RAG 1 API, LOC640611, PPARG, KIT, FOX03,
GO:0010604~positive TCF21, EIS2, SORBSl, S ARCD3, ATG7, SDPR, GPX4, RARB,
GOTER _
regulation of macromolecule 30 0,33629875 AR, BMP2, FOXAl, RBI, CDK4, KITL, PPARGC1A, PPARGCIB, 99,92805636 BP_ALL
metabolic process NOTCHl, PIAS3, JUN, CD81, HIPK2, LOC100047556, NFIC,
APBB1, CLN6
PPARA, ATG10, LOC640611, PPARG, FOX03, TCF21, MEIS2,
GO:0031325~positive SORBSl, S ARCD3, ATG7, SDPR, GPX4, RARB, AR, BMP2,
GOTERM_
regulation of cellular 29 0,42790362 FOXAl, PNPLA2, RBI, CDK4, KITL, PPARGC1A, PPARGCIB, 99,99477354 BP_ALL
metabolic process NOTCHl, PIAS3, JUN, CD81, HIPK2, LOC100047556, NFIC,
APBB1, CLN6
GO:0045944~positive
PPARA, AR, BMP2, FOXAl, PPARG, FOX03, RBI, PPARGC1A,
G0TERM_ regulation of transcription
17 0,42994091 PPARGCIB, NOTCHl, EIS2, SDPR, JUN, HIPK2, 99,99509256 BP ALL from RNA polymerase II
LOC100047556, RARB, NFIC, APBB1
promoter
GO:0051254~positive PPARA, AR, BMP2, FOXAl, PPARG, FOX03, RBI, PPARGC1A,
GOTERM_
regulation of RNA metabolic 19 0,49598885 PPARGCIB, TCF21, NOTCHl, MEIS2, SDPR, GPX4, JUN, HIPK2, 99,99944193 BP_ALL
process LOC100047556, RARB, NFIC, APBB1
PPARA, AR, BMP2, RAG1AP1, FOXAl, PPARG, FOX03, RBI,
GOTERM_ GO:0010628~positive KIT, PPARGC1A, PPARGCIB, TCF21, NOTCHl, MEIS2,
21 0,57144332 99,99996814 BP_ALL regulation of gene expression SMARCD3, SDPR, JUN, HIPK2, LOC100047556, RARB, NFIC,
APBB1
TXNIP, DN T3A, CLN3, WDTCl, GMNN, FOXAl, PPARG,
GO:0031324~negative
GOTERM_ PRDX2, ZEB2, RBI, CDT1, HHEX, TCF21, INSIG2, JUN, BAX,
regulation of cellular 21 0,57519592 99,99997272 BP_ALL HIPK2, GATAD2A, LOC100047575, LOC100047556, RARB,
metabolic process
NFIC, IGFBP3
GO:0045893~positive PPARA, AR, BMP2, FOXAl, PPARG, FOX03, RBI, PPARGC1A,
GOTERM_
regulation of transcription, 18 0,57576309 PPARGCIB, TCF21, NOTCHl, MEIS2, SDPR, JUN, HIPK2, 99,99997336 BP_ALL
DNA-dependent LOC100047556, RARB, NFIC, APBB1
GO:0000122~negative
GOTERM_ regulation of transcription TXNIP, DNMT3A, HHEX, WDTCl, FOXAl, HIPK2, PPARG,
10 0,63429128 99,99999806 BP_ALL from RNA polymerase II LOC100047575, LOC100047556, RBI, RARB, NFIC
promoter
TXNIP, DNMT3A, CLN3, WDTCl, GMNN, FOXAl, PPARG,
GO:00D9892~negative
GOTERM_ PRDX2, ZEB2, RBI, CDT1, TCF21, HHEX, INSIG2, JUN, BAX,
regulation of metabolic 22 0,64804195 99,99999901 BP ALL HIPK2, GATAD2A, LOC100047575, LOC100047556, RARB,
process
NFIC, IGFBP3, APBB1
PPARA, AR, BMP2, FOXAl, PPARG, FOX03, RBI, PPARGC1A,
GOTERM_ GO:0045941~positive
19 0,70207695 PPARGCIB, TCF21, NOTCHl, MEIS2, SMARCD3, SDPR, JUN, 99,99999995 BP_ALL regulation of transcription
HIPK2, LOC100047556, RARB, NFIC, APBB1
PPARA, AR, BMP2, LOC640611, FOXAl, PPARG, FOX03, RBI,
GO:0010557~positive
GOTERM_ CDK4, PPARGC1A, PPARGCIB, TCF21, NOTCHl, MEIS2,
regulation of macromolecule 21 0,71614199 99,99999998 BP ALL SORBSl, SMARCD3, SDPR, JUN, HIPK2, LOC1000475S6, RARB,
biosynthetic process
NFIC, APBB1
GO:0010605~negative TXNIP, DNMT3A, CLN3, WDTCl, GMNN, FOXAl, PPARG,
GOTERM_
regulation of macromolecule 20 0,72030206 ZEB2, RBI, CDT1, TCF21, HHEX, JUN, BAX, HIPK2, GATAD2A, 99,99999998 BP_ALL
metabolic process LOC100047575, LOC100047556, RARB, NFIC, IGFBP3, APBB1
PPARA, AR, BMP2, LOC640611, FOXAl, PPARG, FOX03, RBI,
GO:0009891~positive
GOTERM_ CDK4, PPARGC1A, SEC14L2, PPARGCIB, TCF21, NOTCHl,
regulation of biosynthetic 22 0,7212654 99,99999998 BP_ALL MEIS2, SORBSl, SMARCD3, JUN, SDPR, HIPK2,
process
LOC100047556, RARB, NFIC, APBB1
GO:0045935~positive
PPARA, AR, BMP2, FOXAl, PPARG, FOX03, RBI, PPARGC1A,
GOTERM_ regulation of nucleobase,
20 0,73260929 PPARGCIB, TCF21, NOTCHl, MEIS2, SMARCD3, SDPR, GPX4, 99,99999999 BP_ALL nucleoside, nucleotide and
JUN, HIPK2, LOC100047556, RARB, NFIC, APBB1
nucleic acid metabolic process
GO:0009890~negative TXNIP, DNMT3A, WDTCl, GMNN, FOXAl, PPARG, ZEB2, RBI,
GOTERM_
regulation of biosynthetic 17 0,73474806 CDT1, HHEX, TCF21, INSIG2, HIPK2, GATAD2A, 99,99999999 BP_ALL
process LOC100047575, LOC100047556, RARB, NFIC, APBB1
GO:0045892~negative TXNIP, DNMT3A, WDTCl, PPARG, FOXAl, RBI, HHEX, TCF21,
GOTERM_
regulation of transcription, 12 0,7468337 HIPK2, GATAD2A, LOC100047575, LOC100047556, RARB, 100 BP_ALL
DNA-dependent NFIC
GO:0051253~negative TXNIP, DNMT3A, WDTCl, PPARG, FOXAl, RBI, HHEX, TCF21,
GOTERM_
regulation of RNA metabolic 12 0,75423074 HIPK2, GATAD2A, LOC100047575, LOC100047556, RARB, 100 BP ALL
process NFIC
GO:0010558~negative TXNIP, DNMT3A, WDTCl, GMNN, FOXAl, PPARG, ZEB2, RBI,
GOTERM_
regulation of macromolecule 16 0,76596984 CDT1, HHEX, TCF21, HIPK2, GATAD2A, LOC100047575, 100 BP ALL
biosynthetic process LOC100047556, RARB, NFIC, APBB1
GO:0051173~positive PPARA, AR, BMP2, FOXAl, PPARG, FOX03, RBI, PPARGC1A,
GOTERM_
regulation of nitrogen 20 0,77840497 PPARGCIB, TCF21, NOTCHl, MEIS2, SMARCD3, SDPR, GPX4, 100 BP_ALL
compound metabolic process JUN, HIPK2, LOC100047556, RARB, NFIC, APBB1
PPARA, AR, BMP2, LOC640611, FOXAl, PPARG, FOX03, RBI,
GO:0031328~positive
GOTERM_ CDK4, PPARGC1A, PPARGCIB, TCF21, NOTCHl, MEIS2,
regulation of cellular 21 0,77888592 100 BP_ALL SORBSl, SMARCD3, SDPR, JUN, HIPK2, LOC100047556, RARB,
biosynthetic process
NFIC, APBB1 GO:0045934~negative
TXNIP, DNMT3A, WDTCl, GMNN, FOXAl, PPARG, ZEB2, RBI,
GOTERM_ regulation of nucleobase,
15 0,78166811 CDT1, HHEX, TCF21, HIPK2, GATAD2A, LOC100047575, 100 BP_ALL nucleoside, nucleotide and
LOC100047556, RARB, NFIC
nucleic acid metabolic process
GO:0051172~negative TXNIP, DNMT3A, WDTCl, GMNN, FOXAl, PPARG, ZEB2, RBI,
GOTERM_
regulation of nitrogen 15 0,79358746 CDT1, HHEX, TCF21, HIPK2, GATAD2A, LOC100O47575, 100 BP_ALL
compound metabolic process LOC100047556, RARB, NFIC
GO:0031327~negative TXNIP, DNMT3A, WDTCl, GMNN, FOXAl, PPARG, ZEB2, RBI,
GOTERM_
regulation of cellular 16 0,80109255 CDT1, HHEX, TCF21, INSIG2, HIPK2, GATAD2A, 100 BP_ALL
biosynthetic process LOC100047575, LOC100047556, RARB, NFIC
TXNIP, DNMT3A, WDTCl, PPARG, FOXAl, ZEB2, RBI, HHEX,
GOTERM_ GO:0016481~negative
13 0,85887707 TCF21, HIPK2, GATAD2A, LOC100047575, LOC100047556, 100 BP_ALL regulation of transcription
RARB, NFIC
TXNIP, PPARA, DNMT3A, AR, BMP2, WDTCl, FOXAl, PPARG,
GO:0006357~regulation of
GOTERM_ FOX03, RBI, PPARGC1A, PPARGC1B, HHEX, NOTCH1, MEIS2,
transcription from RNA 21 0,90565184 100 BP_ALL JUN, SDPR, HIPK2, LOC100047575, LOC100047556, RARB,
polymerase II promoter
NFIC, APBB1
TXNIP, DNMT3A, WDTCl, PPARG, FOXAl, ZEB2, RBI, HHEX,
GOTERM_ GO:0010629~negative
13 0,92802266 TCF21, HIPK2, GATAD2A, LOC100047575, LOC100047556, 100 BP_ALL regulation of gene expression
RARB, NFIC
PPARA, HLF, PPARG, E2F8, ZEB2, ELK3, FOX03, MYCL1,
TCF21, MEIS2, HSF2, GPX4, SDPR, CREG1, GATAD2A, OLIGl,
GOTERM_ GO:0051252~regulation of
34 0,99999477 RARB, TXNIP, DNMT3A, AR, BMP2, WDTCl, SMAD7, FOXAl, 100 BP ALL RNA metabolic process
RBI, PPARGC1A, PPARGC1B, HHEX, NOTCH1, JUN, HIPK2,
LOC100047575, LOC100047556, NFIC, APBB1, RERE
PPARA, HLF, PPARG, E2F8, ZEB2, ELK3, FOX03, MYCL1,
TCF21, MEIS2, HSF2, SDPR, CREG1, GATAD2A, OLIGl, RARB,
GOTERM_ GO:0006355~regulation of
33 0,99999575 TXNIP, DNMT3A, AR, BMP2, WDTCl, SMAD7, FOXAl, RBI, loo
BP_ALL transcription, DNA-dependent
PPARGC1A, PPARGC1B, HHEX, NOTCH1, JUN, HIPK2,
LOC100047575, LOC100047556, NFIC, APBB1, RERE
Annotation Enrichment Score:
Cluster 95 0.28388720005383006
Gene
Category Term PValue Genes FDR
Count
GOTERM GO:0042733~embryonic digit
3 0,34393386 GNA12, GASl, LRP4 99,9413487 BP ALL morphogenesis
GOTERM_ GO:0035107~appendage
6 0,52970286 NOTCH1, BAX, GNA12, GASl, RARB, LRP4 99,99983562 BP ALL morphogenesis
GOTERM_ GO:0035108~limb
6 0,52970286 NOTCH1, BAX, GNA12, GASl, RARB, LRP4 99,99983562 BP ALL morphogenesis
GOTERM_ GO:0060173~limb
6 0,56032691 NOTCH1, BAX, GNA12, GASl, RARB, LRP4 99,99994993 BP ALL development
GOTERM_ GO:0048736~appendage
6 0,56032691 NOTCH 1, BAX, GNA12, GASl, RARB, LRP4 99,99994993 BP ALL development
GOTERM_ GO:0030326~embryonic limb
5 0,58302011 NOTCH1, GNA12, GASl, RARB, LRP4 99,99998035 BP ALL morphogenesis
GOTERM_ GO:0035113~embryonic
5 0,58302011 NOTCH1, GNA12, GASl, RARB, LRP4 99,99998035 BP ALL appendage morphogenesis
Annotation Enrichment Score:
Cluster 96 0.26767243328851875
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0060711~labyrinthine
3 0,43378855 WNT2, EGLN1, CYR61 99,99564559 BP ALL layer development
GOTERM_ GO:0001890~placenta
5 0,49665478 WNT2, PPARG, EGLN1, ADA, CYR61 99,9994548 BP ALL development
GOTERM_ GO:0001892~embryonic
3 0,73055009 WNT2, EGLN1, CYR61 99,99999999 BP ALL placenta development
Annotation Enrichment Score:
Cluster 97 0.26528673779077633
Gene
Category Term PValue Genes FDR
Count
RTN4, TTC3, TTL, EPHB2, WNT2, ANK3, ATG7, MAPT, MTPN,
GOTERM_ GO:0048699~generation of RHOC, OLIGl, PAK1, TES, BMP2, MY06, BHLHE22, FOXAl,
27 0,14346619 93,50425366 BP_ALL neurons GASl, GPR98, NOTCHl, EPHA7, FYN, BAX, ID4,
LOC100O47556, STMN1, CLN8, APBB1
JUB, LIMAl, IF3A, MY06, GASl, TTC8, LPINl, GPR98, EPHB2,
GOTERM_ GO:0030030~cell projection
18 0,18612013 NOTCHl, EPHA7, TSC1, ANK3, ATG7, PAK1, STMN1, APBB1, 97,36381939 BP ALL organization
FGD4 RTN4, TTC3, TTL, EPHB2, WNT2, ANK3, ATG7, MAPT, MTPN,
GOTERM_ RHOC, OLIG1, RARB, PAK1, TES, BMP2, MY06, BHLHE22,
GO:0022008~neurogenesis 28 0,18615068 97,36556615 BP_ALL FOXAl, GASl, GPR98, NOTCHl, EPHA7, FYN, BAX, ID4,
LOC100047556, STMNl, CLN8, APBBl
GOTERM_ GO:0032990~cell part MFN2, NOTCHl, EPHA7, KIF3A, ANK3, BAX, GASl, STMNl,
10 0,53060655 99,99984111 BP_ALL morphogenesis APBBl, EPHB2
GOTERM_ GO:0031175~neuron NOTCHl, EPHA7, MY06, ANK3, ATG7, GASl, STMNl, PAK1,
10 0,56458253 99,99995783 BP_ALL projection development APBBl, EPHB2
GOTER _
GO:0007411~axon guidance 5 0,59117867 EPHA7, ANK3, GASl, APBBl, EPHB2 99,99998614 BP ALL
MY06, BHLHE22, FOXAl, GASl, GPR98, EPHB2, NOTCHl,
GOTERM_ GO:0030182~neuron
17 0,60622243 EPHA7, ANK3, MTPN, ATG7, OUG1, ID4, LOC100047556, 99,99999285 BP_ALL differentiation
PAK1, STMNl, CLN8, APBBl
GOTERM_
GO:0007409~axonogenesis 7 0,68245368 NOTCHl, EPHA7, ANK3, GASl, STMNl, APBBl, EPHB2 99,99999984 BP ALL
GOTERM_ GO:0048858~cell projection
8 0,74630503 NOTCHl, EPHA7, KIF3A, ANK3, GASl, STMNl, APBBl, EPHB2 100 BP ALL morphogenesis
GOTERM„ GO:0048812~neuron
7 0,75088871 NOTCHl, EPHA7, ANK3, GASl, STMNl, APBBl, EPHB2 100 BP ALL projection morphogenesis
GO:0048667~cell
GOTERM_
morphogenesis involved in 7 0,77861928 NOTCHl, EPHA7, ANK3, GASl, STMNl, APBBl, EPHB2 100 BP ALL
neuron differentiation
GOTERM_ GO:0048666~neuron NOTCHl, EPHA7, MY06, ANK3, ATG7, GASl, STMNl, PAK1,
11 0,78462643 100 BP ALL development APBBl, GPR98, EPHB2
GO:0000904~cell
GOTERM_
morphogenesis involved in 8 0,78908979 BMP2, NOTCHl, EPHA7, ANK3, GASl, STMNl, APBBl, EPHB2 100 BP_ALL
differentiation
ZEB2, KIT, FOX03, EPHB2, ANK3, ATG7, PAK1, BMP2, MY06,
GOTERM_ GO:0048468~cell FOXAl, BPGM, GASl, KITL, GPR98, KDR, HBA-A1, HBA-A2,
23 0,7972766 100 BP_ALL development REC8, EPHA7, NOTCHl, BAX, STMNl, LOC100047556, APBBl,
LRP4
GOTERM_ GO:0032989~cellular BMP2, LIPA, KIF3A, GASl, EPHB2, MFN2, C09, EPHA7,
13 0,80262951 100 BP ALL component morphogenesis NOTCHl, ANK3, BAX, STMNl, APBBl
GOTERM_ GO:0000902~cell BMP2, NOTCHl, EPHA7, LIPA, KIF3A, ANK3, GASl, STMNl,
10 0,90437816 100 BP ALL morphogenesis APBBl, EPHB2
Annotation Enrichment Score:
Cluster 98 0.2652487450648553
Gene
Category Term PValue Genes FDR
Count
GO:0050954~sensory
GOTERM_
perception of mechanical 6 0,34105499 MY06, FYN, HEXA, HEXB, MPV17, GPR98 99,93663509 BP ALL
stimulus
GOTERM_ GO:0007605~sensory
5 0,46927709 MY06, HEXA, HEXB, MPV17, GPR98 99,99861119 BP ALL perception of sound
GOTERM_ GO:0007600~sensory MY05A, UNC119, MY06, HEXA, HEXB, MPV17, DTNBP1,
13 1 100 BP ALL perception GPR98, LRAT, PDE6D, FYN, CLN8, CLN6
Annotation Enrichment Score:
Cluster 99 0.25841804420180686
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048608~reproductive TCF21, AR, NOTCHl, PSAP, BAX, FOXAl, BIK, LOC100047556,
9 0,17815814 96,86946887 BP ALL structure development FOX03, KDR
GOTERM_ GO:0001541~ovarian follicle
3 0,40450719 BAX, F0X03, KDR 99,98939458 BP_ALL development
GOTERM_ GO:0008584~male gonad
3 0,48990934 AR, BAX, BIK 99,99931036 BP ALL development
GOTERM_ GO:0008406~gonad
5 0,50564741 AR, BAX, BIK, FOX03, KDR 99,99960342 BP ALL development
GOTERM_ GO:0022602~ovulation cycle
3 0,59103215 BAX, F0X03, KDR 99,99998605 BP ALL process
GOTERM_ GO:0048511~rhythmic
5 0,59117867 HLF, LOC640611, BAX, FOX03, CDK4, KDR 99,99998614 BP ALL process
GOTERM_
GO:0042698~ovulation cycle 3 0,60257097 BAX, FOX03, KDR 99,99999158 BP ALL
GOTERM_ GO:0045137~development of
5 0,63809647 AR, BAX, BIK, FOX03, KDR 99,99999839 BP ALL primary sexual characteristics
GOTERM_ GO:0007548~sex
6 0,63896141 TCF21, AR, BAX, BIK, FOX03, KDR 99,99999846 BP ALL differentiation GO:0046546~development of
GOTERM_
primary male sexual 3 0,65656615 AR, BAX, BIK 99,99999936 BP_ALL
characteristics
GOTERM_ GO:0008585~female gonad
3 0,65656615 BAX, FOX03, KDR 99,99999936 BP_ALL development
GO:0046545~development of
GOTERM_
primary female sexual 3 0,69540995 BAX, FOX03, KDR 99,99999992 BP_ALL
characteristics
GOTERM_ GO:0046661~male sex
3 0,69540995 AR, BAX, BIK 99,99999992 BP ALL differentiation
GOTERM_ GO:0046660~female sex
3 0,75459539 BAX, FOX03, KDR 100 BP ALL differentiation
Annotation Enrichment Score:
Cluster 100 0.2531927509881307
Gene
Category Term PValue Genes FDR
Count
WDTC1, AR, KIF3A, TGFBR2, GNA12, EGLN1, ADA, MFN2,
GOTER _ GO:0001701~in utero
14 0,32755527 HBA-Al, WNT2, HBA-A2, NOTCHl, CCNB2, GATAD2A, 99,90935567 BP_ALL embryonic development
LOC100047575, CYR61
GNA12, ZEB2, EGLN1, ADA, WNT2, INSIG2, GATAD2A, RARB,
GOTER _ GO:0009790~em bryon ic CYR61, DNMT3A, AR, B P2, WDTC1, KIF3A, MY06, TGFBR2,
28 0,60967874 99,99999388 BP_ALL development GASl, MFN2, HBA-Al, HHEX, HBA-A2, NOTCHl, CCNB2, LRAT,
TSCl, GTF2IRD1, LOC100047575, CML5, LRP4, CML3
WDTC1, AR, KIF3A, TGFBR2, GNA12, EGLN1, ZEB2, GASl,
GOTERM_ GO:0043009~chordate
17 0,69027775 ADA, MFN2, WNT2, HBA-Al, HBA-A2, NOTCHl, CCNB2, TSCl, 99,9999999 BP_ALL embryonic development
GATAD2A, LOC100047575, CYR61
GO:0009792~embryonic WDTC1, AR, KIF3A, TGFBR2, GNA12, EGLN1, ZEB2, GASl,
GOTERM_
development ending in birth 17 0,70440022 ADA, MFN2, WNT2, HBA-Al, HBA-A2, NOTCHl, CCNB2, TSCl, 99,99999995 BP ALL
or egg hatching GATAD2A, LOC100047575, CYR61
Annotation Enrichment Score:
Cluster 101 0.2530834891773503
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0021549~cerebellum
3 0,43378855 MTPN, ATG7, GASl 99,99564559 BP ALL development
GOTERM_ GO:0022037~metencephalon
3 0,51663107 MTPN, ATG7, GASl 99,99973328 BP ALL development
GOTERM_ GO:0030902~hindbrain
3 0,77676729 MTPN, ATG7, GASl 100 BP ALL development
Annotation Enrichment Score:
Cluster 102 0.25112522340706694
Gene
Category Term PValue Genes FDR
Count
DNMT3A, GNPDA1, HEXA, HEXB, SlOOAll, MFGE8, FOX03,
GOTERM_ GO:0019953~sexual
19 0,35273804 KIT, KITL, HERPUD2, CD9, REC8, AAAS, HSF2, GPX4, BAX, 99,95379505 BP_ALL reproduction
ARSA, BIK, GAL3ST1
GNPDA1, HEXA, HEXB, FOX03, KIT, WNT2, CD9, TCF21, HSF2,
GOTERM_ GPX4, GAL3ST1, TES, DNMT3A, AR, PSAP, FOXAl, TGFBR2,
GO:0000003~reproduction 29 0,37905487 99,97779602 BP ALL SlOOAll, MFGE8, KITL, HERPUD2, KDR, NOTCHl, REC8,
AAAS, BAX, ARSA, BIK, LOC1O0047556, HPGD
GNPDA1, HEXB, FOX03, KIT, WNT2, CD9, TCF21, HSF2, GPX4,
GOTERM_ GO:0022414~reproductive GAL3ST1, TES, DNMT3A, AR, PSAP, FOXAl, TGFBR2, SlOOAll,
28 0,43899288 99,99630062 BP_ALL process MFGE8, KITL, HERPUD2, KDR, NOTCHl, REC8, AAAS, BAX,
ARSA, BIK, LOC100047556, HPGD
GOTERM_ GO:0003006~reproductive AR, PSAP, FOXAl, KIT, FOX03, KITL, KDR, TCF21, NOTCHl,
12 0,54954673 99,99992321 BP ALL developmental process REC8, BAX, BIK, LOC100047556
GO:0048609~reproductive
GOTER _ DNMT3A, AR, HEXB, SlOOAll, FOX03, KIT, HERPUD2, KITL,
process in a multicellular 17 0,64569681 99,99999889 BP_ALL KDR, WNT2, REC8, HSF2, BAX, GPX4, BIK, GAL3ST1, TES
organism
GOTERM_ GO:0032504~multicellular DNMT3A, AR, HEXB, SlOOAll, FOX03, KIT, HERPUD2, KITL,
17 0,64569681 99,99999889 BP ALL organism reproduction KDR, WNT2, REC8, HSF2, BAX, GPX4, BIK, GAL3ST1, TES
GOTERM_ GO:0007276~gamete DNMT3A, HEXB, SlOOAll, KIT, F0X03, HERPUD2, KITL, REC8,
13 0,73540856 99,99999999 BP ALL generation HSF2, BAX, GPX4, BIK, GAL3ST1
GOTER _ GO:0007283~spermatogenesi DNMT3A, REC8, HSF2, GPX4, BAX, SlOOAll, BIK, KIT,
10 0,74530714 100 BP ALL s HERPUD2, GAL3ST1
GOTERM_ GO:0048232~male gamete DNMT3A, REC8, HSF2, GPX4, BAX, SlOOAll, BIK, KIT,
10 0,74530714 100 BP ALL generation HERPUD2, GAL3ST1 Annotation Enrichment Score:
Cluster 103 0.24233341689024068
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0030888~regulation of B
3 0,38959561 FCGR2B, CD81, ADA 99,98358811 BP ALL cell proliferation
GOTERM_ GO:0051249~regulation of
8 0,3978818 FCGR2B, CD81, TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 99,98710675 BP ALL lymphocyte activation
GOTERM_ GO:0002694~regulation of
8 0,46651754 FCGR2B, CD81, TGFBR2, H2-AA, VNNl, PRDX2, CD74, ADA 99,99847803 BP ALL leukocyte activation
GOTERM_ GO:0050865~regulation of
8 0,48006218 FCGR2B, CD81, TGFBR2, H2-AA, VNNl, PR0X2, CD74, ADA 99,99903344 BP ALL cell activation
GOTERM_ GO:0070663~regulation of
4 0,67286638 FCGR2B, CD81, KITL, ADA 99,99999973 BP ALL leukocyte proliferation
GOTER _ GO:0050864~regulation of B
3 0,67646212 FCGR2B, CD81, ADA 99,99999978 BP ALL cell activation
GOTER _ GO:0050670~regulation of
3 0,8537159 FCGR2B, CD81, ADA 100 BP ALL lymphocyte proliferation
GO:0032944~regulation of
GOTERM_
mononuclear cell 3 0,8537159 FCGR2B, CD81, ADA 100 BP_ALL
proliferation
Annotation Enrichment Score:
Cluster 104 0.2350625938012168
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0032101~regulation of
7 0,26205335 IGHG, CLN3, PPARA, FCGR2B, GPX4, TGFBR2, ADA 99,53223321 BP ALL response to external stimulus
GOTERM_ GO:0050727~regulation of
4 0,42874495 IGHG, FCGR2B, GPX4, ADA 99,99490758 BP ALL inflammatory response
GO:0002822~regulation of
adaptive immune response
based on somatic
GOTERM_
recombination of immune 3 0,68605328 IGHG, FCGR2B, ADA 99,99999987 BP_ALL
receptors built from
immunoglobulin superfamily
domains
GOTERM_ GO:0002819~regulation of
3 0,68605328 IGHG, FCGR2B, ADA 99,99999987 BP ALL adaptive immune response
GOTERM_ GO:0031347~regulation of
4 0,81106343 IGHG, FCGR2B, GPX4, ADA 100 BP ALL defense response
GOTERM_ GO:0050776~regulation of
6 0,90628583 IGHG, FCGR2B, BCAR1, H2-AA, CFD, ADA 100 BP ALL immune response
Annotation Enrichment Score:
Cluster 105 0.21808610478342197
Gene
Category Term PVaiue Genes FDR
Count
GOTER _ GO:0042098~T cell
3 0,32845651 FYN, BAX, PRDX2 99,91147668 BP ALL proliferation
GOTERM_ GO:0046651~lymphocyte
3 0,52963898 FYN, BAX, PRDX2 99,99983522 BP ALL proliferation
GOTERM_ GO:0070661~leukocyte
3 0,54240679 FYN, BAX, PRDX2 99,99989863 BP ALL proliferation
G0TERM_ GO:0032943~mononuclear
3 0,54240679 FYN, BAX, PRDX2 99,99989863 BP ALL cell proliferation
GOTERM_ GO:0045321~leukocyte FCGR2B, FYN, BAX, TGFBR2, MS4A1, PRDX2, CD74, ADA,
9 0,70208823 99,99999995 BP ALL activation BLNK
GOTERM_ FCGR2B, FYN, BAX, TGFBR2, MS4A1, PRDX2, ENTPD2, CD74,
GO:0001775~cell activation 10 0,70660205 99,99999996 BP ALL ADA, BLNK
GOTER _ GO:0046649~lymphocyte
7 0,81576403 FYN, BAX, MS4A1, PRDX2, CD74, ADA, BLNK 100 BP ALL activation
GOTER _
GO:0042110~T cell activation 4 0,86910444 FYN, BAX, PRDX2, CD74 100 BP ALL
Annotation Enrichment Score:
Cluster 106 0.19311680161116357
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0043086~negative
5 0,615081 CLN3, TRIB3, RBI, NPR3, CLN8 99,99999522 BP ALL regulation of catalytic activity GO:0044092~negative
GOTERM_
regulation of molecular 6 0,65228711 CLN3, TRIB3, PRDX2, RBI, NPR3, CLN8 99,9999992 BP ALL
function
GO:0051348~negative
GOTERM_
regulation of transferase 3 0,65656615 TRIB3, RBI, CLN8 99,99999936 BP_ALL
activity
Annotation Enrichment Score:
Cluster 107 0.1921055474063639
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051258~protein
4 0,23384378 WNT2, TUBA8, MSTOl, TES 99,09287924 BP ALL polymerization
GOTERM_ GO:0043623~cellular protein
6 0,47400619 WNT2, TUBA8, MSTOl, PAKl, LRP4, TES 99,99881419 BP ALL complex assembly
GOTERM_ GO:0006461~protein complex WNT2, TUBA8, MSTOl, BAX, GPX3, PAKl, ANXA5, LRP4,
10 0,61347783 99,99999485 BP ALL assembly CD74, TES
GOTERM_ GO:0070271~protein complex WNT2, TUBA8, MSTOl, BAX, GPX3, PAKl, ANXA5, LRP4,
10 0,61347783 99,99999485 BP ALL biogenesis CD74, TES
JUB, LIMA1, KIF3A, MSTOl, MY06, SYCE2, ANXA5, CD74,
GOTERM_ GO:0022607~cellular
21 0,67785922 WNT2, CD9, ARHGAP6, TUBA8, SORBSl, BAX, GPX3, CENPV, 99,99999979 BP_ALL component assembly
HIST3H2A, PAKl, LRP4, TES, FGD4
GO:0034622~cellular
GOTERM_
macromolecular complex 8 0,80834925 WNT2, TUBA8, MSTOl, CENPV, HIST3H2A, PAKl, LRP4, TES 100 BP_ALL
assembly
GO:0034621~cellular
GOTERM_ WNT2, TUBA8, MSTOl, CENPV, HIST3H2A, STMN1, PAKl,
macromolecular complex 9 0,80974757 100 BP_ALL LRP4, TES
subunit organization
GOTERM_ GO:0065003~macromolecular WNT2, TUBA8, MSTOl, BAX, GPX3, CENPV, HIST3H2A, PAKl,
12 0,84238988 100 BP ALL complex assembly ANXA5, LRP4, CD74, TES
GOTERM_ GO:0043933~macromolecular MSTOl, ANXA5, CD74, WNT2, TUBA8, BAX, GPX3, CENPV,
13 0,84676437 100 BP ALL complex subunit organization HIST3H2A, PAKl, STMN1, LRP4, TES
JUB, LIMA1, KIF3A, MSTOl, MY06, SYCE2, ANXA5, CD74,
GOTERM_ GO:0044085~cellular
21 0,90839144 WNT2, CD9, ARHGAP6, TUBA8, SORBSl, BAX, GPX3, CENPV, 100 BP ALL component biogenesis
HIST3H2A, PAKl, LRP4, TES, FGD4
Annotation Enrichment Score:
Cluster 108 0.18734816757933878
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0021915~neural tube
6 0,26700705 NOTCHl, KIF3A, TSC1, GATAD2A, ZEB2, GASl 99,58467642 BP ALL development
GOTERM_ GO:0007389~pattern HHEX, NOTCHl, KIF3A, HIPK2, TGFBR2, ZEB2, GASl, PLXNDl,
10 0,84548546 100 BP ALL specification process ENG, LRP4
GOTERM_ GO:0009952~anterior/posteri
5 0,88776861 HHEX, NOTCHl, KIF3A, HIPK2, ZEB2 100 BP ALL or pattern formation
GOTERM_
GO:0003002~regionalization 7 0,88854345 HHEX, NOTCHl, KIF3A, HIPK2, ZEB2, GASl, LRP4 100 BP ALL
Annotation Enrichment Score:
Cluster 109 0.17862838938380465
Gene
Category Term PValue Genes FDR
Count
GO:0032012~regulation of
GOTERM_
ARF protein signal 3 0,47620465 AGFG2, CYTH3, IQSEC1 99,99889871 BP_ALL
transduction
GOTERM_ GO:0043087~regulation of
5 0,54947399 JUB, ARHGAP6, AGFG2, TBC1D19, TBC1D20 99,99992299 BP ALL GTPase activity
GOTER _ GO:0051336~regulation of JUB, ARHGAP6, PTGER3, AGFG2, BAX, CYCS, NPR3, TBC1D19,
9 0,5794389 99,99997715 BP ALL hydrolase activity TBC1D20
GO:0046578~regulation of
GOTERM_
Ras protein signal 7 0,77416491 AGFG2, CYTH3, TBC1D19, TBC1D20, KITL, IQSEC1, FGD4 100 BP_ALL
transduction
GO:0051056~regulation of
GOTERM_ DAB2IP, AGFG2, CYTH3, TBC1D19, TBC1D20, KITL, IQSEC1,
small GTPase mediated signal 8 0,84592993 100 BP_ALL FGD4
transduction
GOTERM_ GO:0032318~regulation of
3 0,8537159 AGFG2, TBC1D19, TBC1D20 100 BP ALL Ras GTPase activity
Annotation Enrichment Score:
Cluster 110 0.1360840464779349
Figure imgf000073_0001
Annotation Enrichment Score:
Cluster 116 0.017173404070944753
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051704~multi-organism WFDC12, AR, STABl, HEXB, TGFBR2, PKLR, PRDX2, COTL1,
11 0,93601459 100 BP ALL process DEFB1, HPGD, CLN8
GOTERM_ GO:0042742~defense
3 0,94411872 WFDC12, STABl, DEFB1 100 BP ALL response to bacterium
GOTERM_ GO:0009617~response to
4 0,96273573 WFDC12, STABl, PRDX2, DEFB1 100 BP ALL bacterium
GOTERM_ GO:0051707~response to
6 0,97251414 WFDC12, STABl, PKLR, PRDX2, COTL1, DEFB1 100 BP ALL other organism
GOTER _ GO:0009607~response to
7 0,9917923 WFDC12, STABl, PKLR, PRDX2, COTL1, DEFB1, HERPUD2 100 BP_ALL biotic stimulus
Annotation Enrichment Score:
Cluster 117 0.006056566954755375
Gene
Category Term PValue Genes FDR
Count
JUB, ADCY6, PPP2R5C, RASL2-9, BBX, INSIG2, KIFAP3, VNN1, RARB, CFD, SGPL1, DAB2IP, RREB1, F8, ZFP467, PPARGC1A, PPARGCIB, VEGFB, IGHG, AD2L1, CD36, PIAS3, JUN, RAB17, CAMK1, EPS8L2, E CN, RALGPS2, ENPP1, GNAI1, RHPN2, ACP5, MY09B, ATP6V0C-PS2, ASB13, OBFC2A, ADA, CD74, EPHB2, ATP6V0C, ADRB3, TCF21, HN T, CDC42EP3, IQSEC1, DNMT3A, BMP2, SMAD7, KLF10, MAOA, TGFBR2, TKT, GAS2, GAS1, TAX1BP3, CSRP3, GAS6, KDR, CIDEC, EPHA7, NOTCH1, RGS3, CML5, COMT1, ENG, CML3, RERE, RTN4, HLF, PPARA, SH3RF1, LIMA1, CPEB2, BCAR1, ZMAT3, PPARG, ZEB2, CDT1, CCNE2, HSF2, GPX4, MAPT, CREG1, ANGPT2, DEDD2, CYR61, CLN3, AR, PIK3C2G, EGFL7, SLC25A4, PI4KA, GPR98, CARDIO, SERPINB9, G6PC, CLN8, CLN6, BID, GPR182, MY05A, ATG10, RAB3D, LOC640611, LOC434624, GNG11, KIT, SEC14L2, MIF, MYCL1, PLCL2, RAB43, SORBS1, GATAD2A, TES, PDK1, PDK2, FZD8, GMNN, PDK4, NPR3, SNAI2, FZD4, FZD7, CPT1A,
PLEKHF1, CCNB2, RAB30, NUPR1, RPS6KA1, FCGR2B, LARGE, ADCY9, PDE2A, STABl, FYN, RAB34, BIK, APBBl, HPGD, TOB2,
GOTERM_ GO:0065007~biological LRP4, BCAR3, LM02, DBF4, GNA12, F2RL1, TCEAL8, FOX03,
269 0,96336776 100 BP_ALL regulation TLR5, LOC100045031, TBC1D19, TCEALl, TTL, APOA4, WNT2,
CISDl, ANK3, SMARCD3, ATG7, STARD8, MS4A1, OLIG1, HBB- Bl, ELTD1, HBB-B2, ATOH8, ZFP503, SLC4A4, ODZ3, MY06, MFGE8, PNPLA2, HDAC11, FGF21, IRS1, HHEX, LRAT,
GTF2IRD1, STMN1, PLXNC1, EIF4E3, RAG1AP1, AGFG2, ELK3, TTC3, PDE6D, MEIS2, CNR2, TEK, MBNL3, PLXND1, ENTPD2, GAL3ST1, RHEBL1, FGD4, BHLHE22, FOXA1, BPGM, KITL, 2410022L05RIK, P2RX4, TSC1, ASNA1, TRIP6, TBC1D20, UBE2E2, HEXA, HEXB, E2F8, HPS4, RHOQ, PRDX2, CASP6, ARHGAP6, SLC1A2, TPP1, SDPR, RHOC, CALCRL, SOX17, NDUFS1, CABLES1, RAMP2, SSBP3, PTGER3, SGK3, CYCS, MTAP4, RBI, CDK4, LPIN1, MFN2, CAPN10, RRAS2, CYP4A31, HIPK2, CD81, H2-AA, LOC100047575, CTSB, PRKCZ, FTL1, FTL2, TNFRSF25, TRIB3, CYTH3, DTNBP1, MTHFS, CD9,
ANXA8, SMOC1, SUCNR1, PPAP2A, GLRX, TXNIP, MS4A4B, WDTC1, LIPA, PSAP, RGS16, ANXA5, RCAN2, CYP4A10, HBA- Al, PEX11A, HBA-A2, ATXN2, BAX, CENPV, LIPG, SETD8, ID4, LOC100047556, NFIC, RDH16, 2700094K13RIK, IGFBP3, RETSAT JUB, ADCY6, PPP2R5C, RASL2-9, BBX, INSIG2, KIFAP3, VNN1,
RARB, CFD, SGPL1, DAB2IP, RREB1, ZFP467, PPARGC1A, PPARGCIB, VEGFB, IGHG, MAD2L1, CD36, PIAS3, JUN, RAB17, CAMK1, EPS8L2, EMCN, RALGPS2, ENPP1, GNAI1, RHPN2, MY09B, ASB13, OBFC2A, ADA, CD74, EPHB2, ADRB3, TCF21, CDC42EP3, IQSECl, DNMT3A, BMP2, SMAD7, LF10, TGFBR2, TKT, GAS2, GAS1, TAX1BP3, CSRP3, GAS6, KDR, CIDEC, EPHA7, NOTCH 1, RGS3, CML5, ENG, RERE, C L3, RTN4, PPARA, SH3RF1, HLF, LIMA1, CPEB2, BCAR1, ZMAT3, PPARG, ZEB2, CDT1, CCNE2, HSF2, GPX4, MAPT, CREG1, ANGPT2, DEDD2, CYR61, CLN3, AR, PIK3C2G, EGFL7, PI4KA, GPR98, CARDIO, SERPINB9, G6PC, CLN8, CLN6, BID, GPR182, MY05A, ATG10, RAB3D, LOC640611, GNG11, KIT, SEC14L2, MIF, YCL1, PLCL2, RAB43, SORBS1, GATAD2A, TES, PDK1, PDK2, FZD8, GMNN, PDK4, NPR3, SNAI2, FZD4, FZD7, CPT1A, PLEKHF1, RAB30, RPS6KA1, FCGR2B, ADCY9, PDE2A, NUPR1,
GOTERM_ GO:0050789~regulation of
242 0,99747488 STAB1, FYN, RAB34, BIK, APBB1, HPGD, TOB2, LRP4, BCAR3, 100 BP_ALL biological process
LM02, DBF4, GNA12, F2RL1, TCEAL8, LOC100045031, TLR5, FOX03, TBC1D19, TCEAL1, TTL, APOA4, WNT2, CISDl, ANK3, SMARCD3, ATG7, STARD8, MS4A1, OLIG1, H BB-B1, ELTD1, HBB-B2, ATOH8, ZFP503, ODZ3, MY06, MFGE8, PNPLA2, FGF21, H DAC11, IRS1, H HEX, GTF2IRD1, STMN1, PLXNC1, EIF4E3, RAG1AP1, AGFG2, ELK3, TTC3, MEIS2, PDE6D, CNR2, TEK, BNL3, PLXND1, RHEBL1, FGD4, BH LHE22, FOXA1, KITL, 2410022L05RIK, TSC1, TRIP6, TBC1D20, UBE2E2, H EXB, E2F8, HPS4, RHOa PRDX2, CASP6, ARHGAP6, SLC1A2, SDPR, RHOC, CALCRL, SOX17, CABLES1, RAMP2, SSBP3, PTGER3, SGK3, CYCS, MTAP4, RBI, CDK4, LPIN1, MFN2, CAPN10, RRAS2, CYP4A31, CD81, HIPK2, H2-AA, LOC100047575, PRKC2, TNFRSF25, TRIB3, CYTH3, MTHFS, CD9, SMOC1, SUCNR1, PPAP2A, GLRX, TXNIP, S4A4B, WDTC1, PSAP, RGS16, ANXA5, RCAN2, CYP4A10, PEXllA, ATXN2, BAX, CENPV, LIPG, ID4, SETD8, LOC100047556, NFIC, 2700094K13RIK, IGFBP3
JUB, ADCY6, PPP2R5C, RASL2-9, BBX, INSIG2, KI FAP3, VNN1, RARB, DAB2IP, RREB1, ZFP467, PPARGC1A, PPARGCIB, VEGFB, IGHG, AD2L1, CD36, PIAS3, JUN, RAB17, CAMK1, EPS8L2, EMCN, RALGPS2, ENPP1, GNAI1, RHPN2, MY09B, ASB13, OBFC2A, ADA, CD74, EPHB2, TCF21, ADRB3,
CDC42EP3, IQSECl, DNMT3A, BMP2, SMAD7, KLFIO, TGFBR2, GAS2, GAS1, TAX1BP3, KDR, CIDEC, EPHA7, NOTCH1, RGS3, CML5, ENG, RERE, CML3, RTN4, PPARA, SH3RF1, HLF, LIMA1, CPEB2, BCAR1, ZMAT3, PPARG, ZEB2, CDT1, CCNE2, HSF2, MAPT, GPX4, CREG1, ANGPT2, DEDD2, CYR61, CLN3, AR, PIK3C2G, EGFL7, PI4KA, GPR98, CARDIO, SERPINB9, CLN8, CLN6, BID, GPR182, MY05A, ATG10, RAB3D, LOC640611, GNG11, KIT, SEC14L2, MIF, MYCL1, PLCL2, RAB43, SORBS1, GATAD2A, TES, PDK1, PDK2, FZD8, GMNN, PDK4, NPR3, SNAI2, FZD4, FZD7, CPT1A, PLEKH F1, RAB30, FCGR2B,
RPS6KA1, ADCY9, PDE2A, NUPR1, FYN, RAB34, BIK, HPGD,
GOTERM_ GO:0050794~regulation of
228 0,99801305 APBB1, TOB2, LRP4, BCAR3, LM02, DBF4, GNA12, F2RL1, 100 BP_ALL cellular process
TCEAL8, LOC100045031, TLR5, F0XO3, TBC1D19, TCEAL1, TTL, WNT2, CISDl, ANK3, SMARCD3, ATG7, STARD8, MS4A1, OLIG1, ELTD1, HBB-B1, ATOH8, ZFP503, HBB-B2, ODZ3, MY06, MFGE8, PNPLA2, FGF21, HDAC11, IRS1, HH EX,
GTF2IRD1, STMN1, PLXNC1, EIF4E3, AGFG2, ELK3, TTC3, MEIS2, PDE6D, CNR2, TE , MBNL3, PLXND1, RHEBL1, FGD4, BHLH E22, FOXA1, KITL, 2410022L05RIK, TSC1, TRIP6,
TBC1D20, HEXB, E2F8, RHOQ, PRDX2, CASP6, ARHGAP6, SDPR, RHOC, CALCRL, SOX17, CABLES1, RAMP2, SSBP3, PTGER3, SGK3, CYCS, MTAP4, RBI, CDK4, LPIN1, MFN2, CAPN10, RRAS2, CYP4A31, CD81, HIPK2, H2-AA,
LOC100047575, PRKCZ, TNFRSF25, TRIB3, CYTH3, MTHFS, CD9, SMOC1, SUCNR1, PPAP2A, GLRX, TXNIP, MS4A4B, WDTC1, PSAP, RGS16, RCAN2, CYP4A10, PEXllA, BAX, LIPG, CENPV, ID4, SETD8, LOC100047556, NFIC, 2700094K13RIK, IGFBP3
Annotation Enrichment Score:
Cluster 118 0.0038049668843465625
Gene
Category Term PValue Genes FDR
Count GNPDA1, RPL13, DBF4, ADCY6, BBX, MPV17, TCEAL8,
LOC100045031, TCEAL1, ST3GAL3, STARD5, INSIG2,
SMARCD3, ATG7, OLIGl, ATOH8, RARB, ZFP503, PDXK, RREBl, UGCG, ZFP467, HDAC11, CHPT1, LPCAT3, PPARGC1A, PPARGC1B, HHEX, PIAS3, GTF2IRD1, JUN, PRODH, HSD17B11, EIF4E3, FARS2, CH KB, ST8SIA3, ATP6V1B2, ELK3, ATP6V0C- PS2, ADA, CD74, ATP6V0B, ATP6V0C, TCF21, PCYT1A,
GAL3ST1, GPD2, DNMT3A, BH LH E22, SMAD7, KLF10, FOXA1,
GOTER _ GO:0009058~biosynthetic FDPS, ACACB, DLAT, PRPSAPl, 2410022L05RIK, P2RX4,
118 0,89395146 100 BP_ALL process NOTCH 1, ST8SIA4, FABP3, FABP5, RERE, CYB5R3, NAMPT,
H LF, PPARA, H EXB, E2F8, PPARG, ZEB2, CDT1, CCNE2, ALASl, HSF2, CHST14, SOX17, DEDD2, PTDSS2, DDC, AR, SSBP3, RBI, PIGQ, PIGP, ST6GALNAC2, ATP6V1A, G6PC, CYP4A31, H IPK2, CD81, UBD, MY05A, ATG10, FUT8, TRIB3, SEC14L2, PBLD, PET112L, MTHFS, AKR1A4, GATAD2A, PTS, PPAP2A, TXNIP, MOGAT2, PDK4, FADS2, SNAI2, APRT, CYP4A10, ADI1,
ACSM3, LARGE, ADCY9, GYG, SETD8, LOC100047556, RDH 16, NFIC, APBB1
GNPDA1, RPL13, DBF4, ADCY6, BBX, MPV17, TCEAL8,
LOC100045031, TCEAL1, ST3GAL3, SMARCD3, ATG7, OLIGl, ATOH8, RARB, ZFP503, PDXK, RREBl, ZFP467, H DAC11, CHPTl, LPCAT3, PPARGCIA, PPARGC1B, HHEX, PIAS3,
GTF2IRD1, JUN, PRODH, EIF4E3, FARS2, CHKB, ST8SIA3, ATP6V1B2, ELK3, ATP6V0C-PS2, ADA, CD74, ATP6V0B, ATP6V0C, TCF21, PCYT1A, GAL3ST1, GPD2, DNMT3A,
BH LHE22, SMAD7, KLF10, FOXA1, FDPS, ACACB, DLAT,
GOTERM_ GO:0044249~cellular
112 0,92952944 PRPSAPl, 2410022L05RIK, P2RX4, NOTCH1, ST8SIA4, FABP3, 100 BP_ALL biosynthetic process
FABP5, RERE, NAMPT, H LF, PPARA, HEXB, E2F8, PPARG, ZEB2, CDT1, CCNE2, ALASl, HSF2, CHST14, SOX17, DEDD2, PTDSS2, DDC, AR, SSBP3, RBI, PIGQ, PIGP, ST6GALNAC2, ATP6V1A, G6PC, CYP4A31, H IPK2, CD81, UBD, MY05A, ATG10, FUT8, TRIB3, SEC14L2, PET112L, MTHFS, AKR1A4, GATAD2A, PPAP2A, PTS, TXNIP, MOGAT2, PDK4, FADS2, SNAI2, APRT, CYP4A10, ADI1, ACSM3, LARGE, ADCY9, GYG, SETD8,
LOC100047556, RDH16, NFIC, APBB1
DBF4, ADCY6, BBX, M PV17, TCEAL8, PTTG1, LOC100045031, DNASE1L3, TCEAL1, DNASE1L1, SMARCD3, ATG7, NT5C2, VNNl, OLIG l, RARB, ZFP503, ATOH8, PABPNl, SGPLl, RREBl, ZFP467, TOPBP1, HDAC11, CHPTl, PPARGCIA, PPARGC1B, GNS, HHEX, DCLRE1A, LRAT, PIAS3, GTF2I RD1, JUN,
LOC100047005, PRODH, ENPP5, RAG1AP1, FARS2, CHKB, ATP6V1B2, ELK3, ATP6V0C-PS2, OBFC2A, ADA, ATP6V0B, ATP6V0C, TCF21, RAD51L1, CSAD, MTPN, PCYT1A, ENTPD2,
GOTERM_ GO:0006807~nitrogen
115 0,98026626 DNMT3A, BHLH E22, SMAD7, MAOA, KLF10, FOXA1, GGH, 100 BP_ALL compound metabolic process
CHI3L1, PPFIBP2, AK2, LOC280487, PRPSAPl, 2410022L05RIK, P2RX4, NOTCH 1, LYVE1, FABP3, COMT1, RERE, FABP5, NAMPT, HLF, PPARA, HEXA, HEXB, E2F8, PPARG, ZEB2, CDT1, CCNE2, ALASl, P4HA2, HSF2, GPX4, CHST14, NSMCE2, SOX17, DEDD2, NDUFS1, CLN3, DDC, AR, SSBP3, RBI, DNASE2B, ATP6V1A, G6PC, CYP4A31, H IPK2, DDB2, CLN6, UPP2, TRIB3, SEC14L2, GATAD2A, PTS, PPAP2A, TXNIP, SNAI2, APRT, CYP4A10, ADI1, ADCY9, SETD8, LOC100047556, NFIC, APBB1
DBF4, ADCY6, BBX, MPV17, TCEAL8, PTTGl, LOC100045031, DNASE1L3, TCEAL1, DNASE1L1, SMARCD3, ATG7, NT5C2, OLIGl, ATOH8, RARB, ZFP503, PABPNl, RREBl, ZFP467, TOPBP1, HDAC11, CHPTl, PPARGCIA, PPARGC1B, HH EX, DCLRE1A, LRAT, PIAS3, GTF2I RD1, JUN, LOC10004700S, PRODH, ENPP5, RAG 1AP1, FARS2, CHKB, ATP6V1B2, ELK3, ATP6V0C-PS2, OBFC2A, ATP6V0B, ADA, ATP6V0C, TCF21,
G0TERM_ GO:0034641~cellular nitrogen CSAD, RAD51L1, MTPN, PCYTIA, ENTPD2, DNMT3A,
104 0,99779159 100 BP ALL compound metabolic process BH LHE22, SMAD7, MAOA, KLF10, FOXA1, GGH, PPFIBP2, AK2,
LOC280487, PRPSAPl, 2410022L05RIK, P2RX4, NOTCH1, FABP3, COMT1, RERE, FABP5, NAMPT, H LF, PPARA, E2F8, PPARG, ZEB2, CDT1, CCNE2, ALASl, HSF2, GPX4, NSMCE2, SOX17, DEDD2, NDUFS1, CLN3, DDC, AR, SSBP3, RBI,
DNASE2B, ATP6V1A, G6PC, CYP4A31, HIPK2, DDB2, UPP2, TRIB3, SEC14L2, GATAD2A, PTS, TXNIP, SNAI2, APRT,
CYP4A10, ADI1, ADCY9, SETD8, LOC100047556, NFIC, APBB1
Figure imgf000077_0001
MKRN1, GRPEL2, RPL13, CNDP2, DBF4, PPP2R5C, BBX,
MPV17, TCEAL8, YLIP, PRKG2, LOC100045031, PTTG1, DNASE1L3, TCEALl, TTL, DNASEILI, WNT2, APOA4, ST3GAL3, SMARCD3, ATG7, OLIG1, ZFP503, RARB, ATOH8, FBX021, CFD, PABPN1, RREB1, ENC1, ZFP467, TOPBP1, HDAC11, PPARGC1A, PPARGC1B, WEE1, GNS, HH EX, IGHG, DCLRE1A, CD36, PIAS3, GTF2IRD1, JUN, BACE1, CAMK1, PPP5C,
LOC100048346, ERMP1, EIF4E3, RAG1AP1, FARS2, MME, ST8SIA3, CTSA, ASB13, ELK3, OBFC2A, CD74, EPHB2, TCF21, SBK1, RAD51L1, TEK, FGD4, DNMT3A, UFSP1, BH LH E22, SMAD7, KLF10, FOXA1, TGFBR2, TAO 3, CHI3L1, PPFIBP2,
GOTERM_ GO:0043170~macromolecule LOC280487, KDR, 2410022L05RIK, EPHA7, NOTCH l, LYVE1,
172 0,9999388 100 BP_ALL metabolic process PLK2, ST8SIA4, PAPPA2, FBX032, UBE2E2, RERE, PPARA, H LF,
SOLH, HEXA, HEXB, PPARG, E2F8, HLCS, PRDX2, ZEB2, CDT1, CCNE2, CASP6, USP18, P4HA2, HSF2, TPP1, GPX4, BAG 2, CHST14, NSMCE2, PAK1, SOX17, DPP7, DPP4, DEDD2, CLN3, CTSZ, AR, SSBP3, SGK3, RBI, MP15, CDK4, PIGQ, PIGP, MMP12, ST6GALNAC2, DNASE2B, G6PC, CAPN10, CYP4A31, CD81, HIPK2, DDB2, UCHL5, UBD, CTSB, CLN8, PMPCB, CLN6, FRK, PRKCZ, ATG10, RAB3D, FUT8, USP2, LOC640611, TRIB3, KIT, SEC14L2, PET112L, PRSS8, PITRM1, TOR1B, CAMK2D, GATAD2A, PPAP2A, TES, PDK1, PTPRB, TXNIP, PDK2, PDK4, SNAI2, CYP4A10, DUSP3, PTP4A3, LARGE, RPS6KA1, FYN, GYG, NLN, SETD8, LOC100047556, NFIC, IGFBP3, APBBl, LRP4
PPARA, HLF, RPL13, DBF4, E2F8, PPARG, BBX, MPV17, ZEB2, TCEAL8, LOC100045031, TCEALl, CDT1, CCNE2, ST3GAL3, HSF2, SMARCD3, ATG7, CHST14, OLIG1, ATOH8, SOX17, RARB, ZFP503, DEDD2, AR, SSBP3, RREB1, ZFP467, RBI,
GO:0034645~cellular HDAC11, PIGQ, PIG P, PPARGC1A, PPARGC1B, ST6GALNAC2,
GOTERM_
macromolecule biosynthetic 69 0,99993911 HHEX, PIAS3, GTF2IRD1, JUN, CYP4A31, H IPK2, UBD, EIF4E3, 100 BP_ALL
process ATG10, FUT8, FARS2, TRI B3, ST8SIA3, ELK3, SEC14L2,
PET112L, TCF21, GATAD2A, TXNIP, DNMT3A, BH LHE22, SMAD7, KLF10, FOXA1, SNAI2, CYP4A10, 2410022L05RIK, NOTCH l, LARGE, ST8SIA4, GYG, SETD8, LOC100047556, NFIC, APBBl, RERE
PPARA, H LF, RPL13, DBF4, E2F8, PPARG, BBX, MPV17, ZEB2, TCEAL8, LOC100045031, TCEALl, CDT1, CCNE2, ST3GAL3, HSF2, SMARCD3, ATG7, CHST14, OLIG1, ATOH8, SOX17, RARB, ZFP503, DEDD2, AR, SSBP3, RREB1, ZFP467, RBI, H DAC11, PIGQ, PIG P, PPARGC1A, PPARGC1B, ST6GALNAC2,
GOTERM_ GO:0009059~macromolecule
69 0,99994734 HH EX, PIAS3, GTF2IRD1, JUN, CYP4A31, H IPK2, UBD, EIF4E3, 100 BP ALL biosynthetic process
ATG10, FUT8, FARS2, TRIB3, ST8SIA3, ELK3, SEC14L2,
PET112L, TCF21, GATAD2A, TXNIP, DNMT3A, BH LH E22, SMAD7, KLF10, FOXA1, SNAI2, CYP4A10, 2410022L05RIK, NOTCH l, LARGE, ST8SIA4, GYG, SETD8, LOC100047556, NFIC, APBBl, RERE
NAMPT, PPARA, HLF, DBF4, E2F8, ADCY6, PPARG, BBX, PV17, ZEB2, TCEAL8, LOC100045031, PTTG1, DNASE1L3, TCEALl, DNASEILI, CDT1, CCNE2, HSF2, SMARCD3, GPX4, NT5C2, NSMCE2, OLIG1, ATOH8, SOX17, RARB, ZFP503, DEDD2, NDUFS1, PABPN1, AR, SSBP3, RREB1, ZFP467,
TOPBP1, RBI, H DAC11, PPARGC1A, PPARGC1B, DNASE2B,
GO:0006139~nucleobase,
GOTER _ ATP6V1A, HH EX, DCLRE1A, PIAS3, GTF2IRD1, JUN, CYP4A31, nucleoside, nucleotide and 84 0,99998197 100 BP ALL HIPK2, DDB2, LOC1O0047005, ENPP5, RAG1AP1, FARS2,
nucleic acid metabolic process
TRIB3, UPP2, ATP6V1B2, ELK3, ATP6V0C-PS2, OBFC2A, SEC14L2, ATP6V0B, ADA, ATP6V0C, TCF21, RAD51L1,
GATAD2A, ENTPD2, TXNIP, DNMT3A, BH LH E22, SMAD7, KLF10, FOXA1, PPFIBP2, LOC280487, AK2, SNAI2, PRPSAP1, APRT, CYP4A10, 2410022L05RIK, NOTCH l, ADCY9, SETD8, LOC100047556, NFIC, APBBl, RERE
HLF, PPARA, E2F8, ADCY6, PPARG, BBX, ZEB2, TCEAL8, PRDX2, LOC100045031, FOX03, TCEALl, CDT1, HSF2,
SMARCD3, SDPR, GPX4, CREG1, OLIG1, AT0H8, ZFP503, RARB, SOX17, CALCRL, DEDD2, SSBP3, AR, RREB1, ZFP467,
GO:0019219~regulation of
RBI, HDAC11, PPARGC1A, PPARGC1B, HHEX, PIAS3,
GOTERM_ nucleobase, nucleoside,
65 0,99998286 GTF2IRD1, JUN, CYP4A31, HIPK2, LOC100047575, TRIB3, 100 BP_ALL nucleotide and nucleic acid
ELK3, SEC14L2, MYCL1, TCF21, ADRB3, MEIS2, GATAD2A, metabolic process
TXNIP, DNMT3A, WDTC1, BMP2, BHLHE22, S AD7, GMNN, KLF10, FOXA1, NPR3, SNAI2, CYP4A10, 2410022L05RIK, NOTCHl, ADCY9, SETD8, ID4, LOC100047556, NFIC, APBBl, RERE PPARA, HLF, CPEB2, E2F8, ADCY6, PPARG, BBX, ZEB2, TCEAL8,
PRDX2, LOC100045031, FOX03, TCEAL1, CDT1, INSIG2, HSF2, SMARCD3, SDPR, CREG1, OLIG1, ATOH8, ZFP503, RARB, SOX17, CALCRL, DEDD2, SSBP3, AR, RREB1, ZFP467, RBI, HDAC11, CDK4, PPARGC1A, PPARGC1B, HHEX, PIAS3,
GOTERM_ GO:0031326~regulation of
69 0,99998313 GTF2IRD1, JUN, CYP4A31, HIPK2, LOC100047575, EIF4E3, 100 BP_ALL cellular biosynthetic process
LOC640611, TRIB3, ELK3, SEC14L2, MYCLl, TCF21, ADRB3, MEIS2, SORBS1, GATAD2A, TXNIP, DNMT3A, WDTC1, BMP2, BHLHE22, SMAD7, GMNN, KLF10, FOXA1, NPR3, SNAI2, CYP4A10, 2410022L05RIK, NOTCH 1, ADCY9, SETD8, ID4, LOC100047556, NFIC, APBB1, RERE
PPARA, HLF, CPEB2, E2F8, ADCY6, PPARG, BBX, ZEB2, TCEAL8, PRDX2, LOC100045031, FOX03, TCEAL1, CDT1, INSIG2, HSF2, SMARCD3, SDPR, CREG1, OLIG1, ATOH8, ZFP503, RARB, SOX17, CALCRL, DEDD2, SSBP3, AR, RREB1, ZFP467, RBI, HDAC11, CDK4, PPARGC1A, PPARGC1B, HHEX, PIAS3,
GOTERM_ GO:0009889~regulation of
69 0,9999858 GTF2IRD1, JUN, CYP4A31, HIPK2, LOC100047575, EIF4E3, 100 BP_ALL biosynthetic process
LOC640611, TRIB3, ELK3, SEC14L2, MYCLl, TCF21, ADRB3, MEIS2, SORBS1, GATAD2A, TXNIP, DNMT3A, WDTC1, BMP2, BHLHE22, SMAD7, GMNN, KLF10, FOXA1, NPR3, SNAI2, CYP4A10, 2410022L05RIK, NOTCH1, ADCY9, SETD8, ID4, LOC100047556, NFIC, APBB1, RERE
MKRN1, GRPEL2, RPL13, DBF4, PPP2R5C, BBX, MPV17, TCEAL8, MYLIP, PRKG2, PTTG1, LOC100045031, DNASE1L3, TCEAL1, TTL, DNASE1L1, WNT2, APOA4, ST3GAL3, SMARCD3, ATG7, OLIG1, ZFP503, RARB, ATOH8, FBX021, PABPN1, RREB1, ENC1, ZFP467, TOPBP1, HDAC11, PPARGC1A,
PPARGC1B, WEE1, HHEX, DCLRE1A, CD36, PIAS3, GTF2IRD1, JUN, BACE1, CAMK1, PPP5C, LOC100048346, EIF4E3,
RAG1AP1, FARS2, ST8SIA3, ASB13, ELK3, OBFC2A, CD74, EPHB2, TCF21, SBK1, RAD51L1, TEK, FGD4, DNMT3A,
GO:0044260~cellular BHLHE22, UFSP1, SMAD7, KLF10, FOXA1, TGFBR2, TAOK3,
GOTERM_
macromolecule metabolic 146 0,99998727 PPFIBP2, LOC280487, KDR, 2410022L05RIK, EPHA7, NOTCH1, 100 BP ALL
process PLK2, ST8SIA4, FBX032, UBE2E2, RERE, HLF, PPARA, HEXB,
PPARG, E2F8, HLCS, PRDX2, ZEB2, CDT1, CCNE2, USP18, P4HA2, HSF2, GPX4, CHST14, NSMCE2, PAK1, SOX17, DEDD2, CLN3, AR, SSBP3, SGK3, RBI, CDK4, PIGQ, PIGP, ST6GALNAC2, DNASE2B, G6PC, CYP4A31, HIPK2, CD81, UCHL5, DDB2, UBD, CLN8, CLN6, FRK, PRKCZ, ATG10, RAB3D, FUT8, USP2,
LOC640611, TRIB3, KIT, SEC14L2, PET112L, TOR1B, CAMK2D, GATAD2A, PPAP2A, TES, PDK1, PTPRB, TXNIP, PDK2, PDK4, SNAI2, CYP4A10, DUSP3, PTP4A3, LARGE, RPS6KA1, FYN, GYG, SETD8, LOC100047556, NFIC, IGFBP3, APBB1, LRP4
HLF, PPARA, E2F8, ADCY6, PPARG, BBX, ZEB2, TCEAL8,
PRDX2, LOC100045031, FOX03, TCEAL1, CDT1, HSF2,
SMARCD3, SDPR, GPX4, CREG1, OLIG1, ATOH8, ZFP503, RARB, SOX17, CALCRL, DEDD2, SSBP3, AR, RREB1, ZFP467,
GO:0051171~regulation of RBI, HDAC11, PPARGC1A, PPARGC1B, HHEX, PIAS3,
GOTER _
nitrogen compound metabolic 65 0,99998818 GTF2IRD1, JUN, CYP4A31, HIPK2, LOC100047575, TRIB3, 100 BP_ALL
process ELK3, SEC14L2, MYCLl, TCF21, ADRB3, MEIS2, GATAD2A,
TXNIP, DNMT3A, WDTC1, BMP2, BHLHE22, SMAD7, GMNN, KLF10, FOXA1, NPR3, SNAI2, CYP4A10, 2410022L05RIK, NOTCH1, ADCY9, SETD8, ID4, LOC100047556, NFIC, APBB1, RERE
PPARA, HLF, CPEB2, E2F8, PPARG, HPS4, BBX, ZEB2, TCEAL8, PRDX2, LOC100045031, FOX03, TCEAL1, HSF2, SMARCD3, SDPR, GPX4, CREG1, OLIG1, ATOH8, RARB, SOX17, ZFP503, DEDD2, CLN3, SSBP3, AR, RREB1, ZFP467, RBI, HDAC11, CDK4, PPARGC1A, PPARGC1B, HHEX, G6PC, PIAS3, GTF2IRD1,
GOTER _ GO:0010468~regulation of
67 0,99998821 JUN, CYP4A31, HIPK2, LOC100047575, EIF4E3, RAG1AP1, 100 BP ALL gene expression
LOC640611, TRIB3, KIT, ELK3, SEC14L2, MYCLl, TCF21, MEIS2, GATAD2A, TXNIP, DNMT3A, WDTC1, BMP2, BHLHE22,
SMAD7, KLF10, FOXA1, SNAI2, CYP4A10, 2410022L05RIK, NOTCH1, SETD8, ID4, LOC100047556, NFIC, APBB1, RERE, TOB2
PPARA, HLF, PPARG, E2F8, ZEB2, ELK3, FOX03, MYCLl, TCF21, MEIS2, HSF2, GPX4, SDPR, CREG1, GATAD2A, OLIG1,
GOTERM_ GO:0051252~regulation of
34 0,99999477 RARB, TXNIP, DNMT3A, AR, BMP2, WDTC1, SMAD7, FOXA1, 100 BP_ALL RNA metabolic process
RBI, PPARGC1A, PPARGC1B, HHEX, NOTCH1, JUN, HIPK2, LOC100047575, LOC100047556, NFIC, APBB1, RERE PPARA, HLF, PPARG, E2F8, ZEB2, ELK3, FOX03, MYCLl,
TCF21, MEIS2, HSF2, SDPR, CREGl, GATAD2A, OLIGl, RARB,
GOTERM_ GO:0006355~regulation of
33 0,99999575 TXNIP, DNMT3A, AR, BMP2, WDTC1, SMAD7, FOXA1, RBI, 100 BP_ALL transcription, DNA-dependent
PPARGC1A, PPARGC1B, HHEX, NOTCH1, JUN, HIPK2,
LOC100047575, LOC100047556, NFIC, APBB1, RERE
PPARA, HLF, CPEB2, E2F8, PPARG, BBX, ZEB2, TCEAL8, PRDX2, LOC100045031, FOX03, TCEAL1, CDT1, HSF2, SMARCD3, SDPR, CREGl, OLIGl, ATOH8, ZFP503, RARB, SOX17, DEDD2, SSBP3, AR, RREB1, ZFP467, RBI, HDAC11, CDK4, PPARGC1A,
GO:0010556~regulation of
G0TERM_ PPARGC1B, HHEX, PIAS3, GTF2IRD1, JUN, CYP4A31, HIPK2, macromolecule biosynthetic 63 0,99999691 100 BP ALL LOC100047575, EIF4E3, LOC640611, TRIB3, ELK3, SEC14L2, process
MYCLl, TCF21, MEIS2, SORBS1, GATAD2A, TXNIP, DNMT3A, WDTC1, BMP2, BHLHE22, SMAD7, GMNN, KLF10, FOXA1, SNAI2, CYP4A10, 2410022L05RIK, NOTCH1, SETD8, ID4, LOC100047556, NFIC, APBB1, RERE
HLF, PPARA, E2F8, PPARG, BBX, ZEB2, TCEAL8, PRDX2, LOC100045031, FOX03, TCEAL1, HSF2, SMARCD3, SDPR, CREGl, OLIGl, ATOH8, ZFP503, RARB, SOX17, DEDD2, SSBP3, AR, RREB1, ZFP467, RBI, HDAC11, PPARGC1A, PPARGC1B,
GOTER _ GO:0045449~regulation of
57 0,99999801 HHEX, PIAS3, GTF2IRD1, JUN, HIPK2, CYP4A31, 100 BP_ALL transcription
LOC100047575, TRIB3, ELK3, SEC14L2, MYCLl, TCF21, MEIS2, GATAD2A, TXNIP, DNMT3A, BMP2, WDTC1, BHLHE22, SMAD7, KLF10, FOXA1, SNAI2, 2410022L05RIK, CYP4A10, NOTCH1, SETD8, ID4, LOC100047556, NFIC, APBB1, RERE
PPARA, HLF, RPL13, E2F8, PPARG, BBX, MPV17, ZEB2,
TCEAL8, LOC100045031, TCEAL1, HSF2, S ARCD3, GPX4, OLIGl, ATOH8, ZFP503, RARB, 50X17, CFD, DEDD2, PABPNl, CLN3, SSBP3, AR, RREB1, ZFP467, RBI, HDAC11, PPARGC1A,
GOTER _
GO:0010467~gene expression 59 1 PPARGC1B, IGHG, HHEX, PIAS3, JUN, GTF2IRD1, HIPK2, 100 BP_ALL
CYP4A31, UBD, EIF4E3, FARS2, TRIB3, ELK3, SEC14L2,
PET112L, TCF21, GATAD2A, TXNIP, DNMT3A, BHLHE22, SMAD7, KLF10, FOXAl, SNAI2, 2410022L05RIK, CYP4A10, NOTCH1, SETD8, LOC100047556, NFIC, APBB1, RERE
Table III
Figure imgf000081_0001
FOXA3, F13A1, TIRAP, TLR2, PDIA5, CXCL11, CXCL10, HSPH1,
MYD88, ALAS2, SAA2, LOC100048018, ANG, SAAl, IL1RAP,
PROZ, CREB3L2, CFH, ILIB, LBP, DNAJC3, MX2, NFKBIZ, BCL10,
PLD1, F10, HSP90AA1, RELA, PRKAB1, SAA3, SAA4, IFI47,
RAD52, TACC3, TAT, AHR, CD163, C8A, ADRB2, SERPINA3N,
C4BP, THBD, BTG2, LOC640441, SERPINF2, HSPB8, CCR2,
GOTERM_ GO:0006950~response to
91 3,62E-13 RIPK2, GADD45A, SRXN1, SERP1, CXCL1, RAD23B, IL1R1, CCL2, 6,30E-10 BP ALL stress
CXCL5, C3, CCR1, SKIV2L, HSPA1A, HSPA1B, EDEM1, LEAP2,
ARG1, LOC100045000, SERPINA1B, FGA, SERPINAIA, BCL3,
TRP53INP1, STK19, RUNX1, THBS1, FN1, B4GALT1, CFB,
MAP2K3, TREX1, CCL19, CHI3L3, SMAD1, CHI3L4, BIRC2,
BRCA1, STAT3, HYOU1, ORM1, CXCL13, AVPR1A, HBEGF,
DNAJB1, SCARA5, CD14, ORM2, ORM3
Annotation Enrichment Score:
Cluster 2 5.511060319715296
Gene
Category Term PValue Genes FDR
Count
CYP51, HSD3B2, HSD3B3, HSD3B6, HSD17B2, MVD, HMGCR,
GOTERM_ GO:0006694~steroid
19 1,91E-11 HSD3B5, LSS, PMVK, FDFTl, SC4MOL, CYP7B1, CYP17A1, 3.33E-08 BP_ALL biosynthetic process
CH25H, DHCR7, SDR42E1, IDI1, AKR1D1
CYP51, HSD3B2, HSD3B3, HSD17B2, HSD3B6, MVD, HMGCR,
GOTERM_ GO:0008202~steroid HSD3B5, LSS, ABCAl, PMVK, SC4MOL, FDFTl, SERPINA6, SAAl,
27 4,31E-11 7,51E-08 BP_ALL metabolic process CH25H, APOF, LCAT, SULT1A1, DHCR7, OSBPL9, CYP7B1,
CYP17A1, SDR42E1, IDI1, NR5A2, AKR1D1
CYP51, HSD3B2, HSD3B3, HSD17B2, HSD3B6, MVD, HMGCR,
HSD3B5, LSS, PMVK, SC4MOL, FDFTl, ISYNA1, ANG, CH25H,
GOTERM_ GO:0008610~lipid
31 5,14E-08 DHCR7, ALOX5AP, ELOVL3, 2010111I01RIK, B4GALNT1, PLD1, 8,95E-05 BP_ALL biosynthetic process
SCD2, LPGAT1, PRKAB1, ACLY, BRCA1, CYP7B1, CYP17A1,
SDR42E1, IDI1, AKR1D1
GOTERM_ GO:0016125~sterol metabolic CYP51, MVD, HMGCR, ABCAl, PMVK, FDFTl, SC4MOL, CYP7B1,
14 l,97E-06 0,003436581 BP_ALL process SAAl, LCAT, DHCR7, APOF, CH25H, IDI1
GOTERM_ GO:0008203~cholesterol CYP51, MVD, HMGCR, ABCAl, PMVK, FDFTl, CYP7B1, SAAl,
13 4,14E-06 0,007216703 BP ALL metabolic process LCAT, DHCR7, APOF, CH25H, 1011
GOTERM_ GO:0016126~sterol CYP51, MVD, HMGCR, CH25H, DHCR7, PMVK, IDI1, SC4MOL,
9 5,55E-06 0,009659042 BP ALL biosynthetic process FDFTl
HSD3B2, CYP51, ACOX2, HACLl, HSD3B3, MVD, RBPl, HSD3B6,
HSD17B2, HMGCR, CREM, HSD3B5, LSS, ABCAl, PMVK, FDFTl,
SC4M0L, ISYNA1, SAAl, GATA6, ANG, SERPINA6, CH25H,
GOTERM_ GO:0006629~lipid metabolic
48 7,41E-06 DHCR7, ELOVL3, SULT1A1, LCAT, ALOXSAP, APOF, ACSL4, 0,012915141 BP ALL process
2010111I01RIK, B4GALNT1, PLD1, SCD2, LPGAT1, OSBPL9,
ACNAT2, IL1RN, PRKAB1, ACLY, BRCA1, CYP7B1, SLC35C1,
CYP17A1, SDR42E1, NR5A2, IDI1, AKR1D1
CYP51, LDHA, MVD, HMGCR, PFKFB2, GNPNAT1, HK2, ABCAl,
GOTERM_ GO:0006066~alcohol PMVK, SC4MOL, FDFTl, ISYNA1, SAAl, CH25H, HDC, DHCR7,
29 5,11E 05 0,088978866 BP_ALL metabolic process APOF, ADH4, LCAT, GNMT, B4GALT1, CMAH, MOXD1, CYP7B1,
ATF4, SDS, IDI1, DCXR, SERP1
GOTERM_ GO:0006695~cholesterol
7 9,83 E-05 CYP51, MVD, HMGCR, DHCR7, PMVK, IDI1, FDFTl 0,171108629 BP ALL biosynthetic process
GOTERM_ GO:0008299~isoprenoid
4 0,038314846 MVD, HMGCR, IDI1, FDFTl 49,36484908 BP ALL biosynthetic process
GOTERM_ GO:0006720~isoprenoid
5 0,087203906 MVD, RBPl, HMGCR, IDI1, FDFTl 79,59413485 BP_ALL metabolic process
Annotation Enrichment Score:
Cluster 3 5.362593898465161
Gene
Category Term PValue Genes FDR
Count
SERPINA3K, SERPINA3N, SERPINA3M, MCL1, SERPINA1B,
GOTERM_ GO:0034097~response to
12 4,77E-09 SERPINA3G, SERPINAIA, SERPINAID, SERPINAIC, RIPK2, 8,31E-06 BP_ALL cytokine stimulus
SERPINA1E, 1100001G20RIK
MCL1, SKIV2L, TLR2, AGXT, EDEM1, FOS, MYD88, SERPINA1B,
SERPINAIA, LCAT, SERPINAID, SERPINAIC, CREB3L2, ILIB, FAS,
GOTERM_ GO:0010033~response to LBP, STK19, DNAJC3, ADAM9, EGR1, BCL10, HSP90AA1, APCS,
41 7,90E-07 0,001376254 BP_ALL organic substance CFB, PTPN2, RELA, TGFBR1, SERPINA1E, RCAN1, TAT,
1100001G20RIK, STAT3, SERPINA3K, SERPINA3N, SERPINA3M,
THBD, SERPINA3G, RIPK2, PTPN1, CD14, SERP1
PTPN2, TGFBR1, RCAN1, SERPINA1E, TAT, AGXT, STAT3,
GOTERM_ GO:0009725~response to SERPINA3K, SERPINA3N, SERPINA3M, SERPINA1B, SERPINA3G,
19 l,52E-05 0,026454428 BP_ALL hormone stimulus SERPINAIA, SERPINAID, LCAT, SERPINAIC, PTPN1, FAS,
ADAM9 PTPN2, TGFBR1, RCAN1, SERPINA1E, TAT, AGXT, STAT3,
GOTER _ GO:0009719~response to SERPINA3K, SERPINA3N, SERPINA3M, SERPINAIB, SERPINA3G,
19 6,56E-05 0,11419674 BP_ALL endogenous stimulus SERPINA1A, SERPINA1D, LCAT, SERPINA1C, PTPN1, FAS,
ADAM9
SERPINA3K, SERPINA3N, SERPINA3M, SERPINAIB, SERPINA3G,
GOTERM_ GO:0043434~response to
12 4,09E-04 SERPINA1A, PTPN2, SERPINA1D, SERPINA1C, SERPINA1E, 0,710780534 BP_ALL peptide hormone stimulus
PTPN1, STAT3
Annotation Enrichment Score:
Cluster 4 3.891890452699098
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0042089~cytokine
6 4,82E-05 IRF9, MYD88, GADD45G, IL1RAP, PAWR, PCSK5 0,084001735 BP ALL biosynthetic process
GOTERM_ GO:0042107~cytokine
6 7,29E-05 IRF9, YD88, GADD45G, IL1RAP, PAWR, PCSK5 0,126959298 BP_ALL metabolic process
GOTERM_ GO:0001816~cytokine
8 6,00E-04 IRF9, YD88, REL, GADD45G, IL1RAP, PAWR, LBP, PCSK5 1,039605236 BP_ALL production
Annotation Enrichment Score:
Cluster 5 3.7358387163840985
Gene
Category Term PValue Genes FDR
Count
ACOX2, HACL1, ALDH1L1, RBP1, GLUDl, F13A1, ASNS, PSPH,
AGXT, SC4 OL, AFMID, ARG1, T0O2, CH25H, HOC, ELOVL3,
GOTERM_ GO:0006082~organic acid ALOX5AP, GNMT, ACSL4, 2010111I01RIK, PLD1, SCD2,
40 5,79E-07 0,001009173 BP_ALL metabolic process LOC100045567, ACNAT2, HAL, CMAH, PRKAB1, TAT,
LOC100044878, MOXD1, BRCAl, CYP7B1, TARS, ATF4, CTH,
SDS, GFPT1, NR5A2, A R1D1, CBS
ACOX2, HACL1, ALDH1L1, RBP1, GLUDl, F13A1, ASNS, PSPH,
AGXT, SC4MOL, AFMID, ARG1, TD02, CH25H, HDC, ALOX5AP,
GOTERM_ GO:0043436~oxoacid
39 1,47 E-06 ELOVL3, GNMT, ACSL4, 2010111I01RIK, PLD1, SCD2, ACNAT2, 0,002557642 BP_ALL metabolic process
HAL, CMAH, PRKAB1, TAT, LOC100044878, MOXD1, BRCAl,
CYP7B1, TARS, ATF4, CTH, SDS, GFPT1, NR5A2, AKR1D1, CBS
ACOX2, HACL1, ALDH1L1, RBP1, GLUDl, F13A1, ASNS, PSPH,
AGXT, SC4MOL, AFMID, ARG1, TD02, CH25H, HDC, ALOX5AP,
GOTERM_ GO:0019752~carboxylic acid
39 l,47E-06 ELOVL3, GNMT, ACSL4, 2010111I01RIK, PLD1, SCD2, ACNAT2, 0,002557642 BP_ALL metabolic process
HAL, CMAH, PRKAB1, TAT, LOC100044878, MOXD1, BRCAl,
CYP7B1, TARS, ATF4, CTH, SDS, GFPT1, NR5A2, AKR1D1, CBS
ACOX2, HACL1, ALDH1L1, RBP1, GLUDl, F13A1, ASNS, PSPH,
AGXT, SC4MOL, AFMID, ARG1, TD02, CH25H, HDC, ALOX5AP,
GOTERM_ GO:0042180~cellular ketone
39 2,63E-06 ELOVL3, GNMT, ACSL4, 2010111I01RIK, PLD1, SCD2, ACNAT2, 0,004587038 BP ALL metabolic process
HAL, CMAH, PRKAB1, TAT, LOC100044878, MOXD1, BRCAl,
CYP7B1, TARS, ATF4, CTH, SDS, GFPT1, NR5A2, AKR1D1, CBS
PL01, SCD2, PRKAB1, ASNS, PSPH, AGXT, LOC100044878,
GOTERM_ GO:0046394~carboxylic acid
17 2,76E-05 BRCAl, SC4MOL, CYP7B1, CTH, CH25H, ALOX5AP, ELOVL3, 0,047982262 BP ALL biosynthetic process
AKR1D1, 2010111I01RIK, CBS
PLD1, SCD2, PRKAB1, ASNS, PSPH, AGXT, LOC100044878,
GOTERM_ GO:0016053~organic acid
17 2,76E-05 BRCAl, SC4MOL, CYP7B1, CTH, CH25H, ALOX5AP, ELOVL3, 0,047982262 BP_ALL biosynthetic process
AKR1D1, 2010111I01RIK, CBS
GOTER _ GO:0006520~cellular amino F13A1, GLUDl, HAL, ASNS, PSPH, TAT, AGXT, MOXD1, AFMID,
18 3,25E-04 0,564227813 BP ALL acid metabolic process TARS, ARG1, CTH, TD02, SDS, HDC, GFPT1, GNMT, CBS
F13A1, GLUDl, ASNS, PSPH, AGXT, AFMID, ARG1, TD02, ITIHl,
GOTERM_ GO:0009308~amine
25 6,02 E-04 HDC, ITIH4, ITIH2, GNMT, ITIH3, HAL, CHI3L3, CHI3L4, TAT, 1,043628547 BP_ALL metabolic process
MOXD1, TARS, CTH, CHID1, SDS, GFPT1, CBS
ACOX2, HACL1, SCD2, ALDH1L1, RBP1, ACNAT2, PRKAB1,
GOTERM_ GO:0032787~monocarboxylic
20 0,00235552 AGXT, BRCAl, SC4MOL, CYP7B1, ATF4, SDS, CH25H, ALOX5AP, 4,024664725 BP_ALL acid metabolic process
ELOVL3, NR5A2, ACSL4, AKR1D1, 2010111I01RIK
GOTERM_ GO:0044106~cellular amine F13A1, GLUDl, HAL, ASNS, PSPH, TAT, AGXT, MOXD1, AFMID,
18 0,007428662 12,18010261 BP ALL metabolic process TARS, ARG1, CTH, TD02, SDS, HDC, GFPT1, GNMT, CBS
GOTERM_ GO:0006633~fatty acid SCD2, ELOVL3, CH25H, ALOX5AP, PRKAB1, 2010111I01RIK,
8 0,021272035 31,23897549 BP ALL biosynthetic process BRCAl, SC4MOL
GO:0006519~cellular amino
GOTERM_ F13A1, GLUDl, HAL, ASNS, PSPH, TAT, AGXT, MOXD1, AFMID,
acid and derivative metabolic 18 0,028065586 39,09547958 BP_ALL TARS, ARG1, CTH, TD02, SDS, HDC, GFPT1, GNMT, CBS
process
GOTERM_ GO:0006631~fatty acid ACOX2, HACL1, SCD2, ACNAT2, ELOVL3, CH25H, ALOX5AP,
12 0,053262247 61,45681274 BP ALL metabolic process PRKAB1, ACSL4, 2010111I01RIK, BRCAl, SC4MOL
Annotation Enrichment Score:
Cluster 6 2.900114045957533
Gene
Category Term PValue Genes FDR
Count
Figure imgf000084_0001
Annotation Enrichment Score:
Cluster 10 2.014114263081338
Gene
Category Term PValue Genes FDR
Count
GOTERM_ ST3GAL1, B4GALT1, ST6GAL1, STT3A, SERPINAIB, B3GALT1,
GO:0070085~glycosylation 10 0,004028983 6,790653547 BP ALL SERPINA1A, CES6, SERPINA1C, SERP1
GOTERM_ GO:0006486~protein amino ST3GAL1, B4GALT1, ST6GAL1, STT3A, SERPINAIB, B3GALT1,
10 0,004028983 6,790653547 BP ALL acid glycosylation SERPINA1A, CES6, SERPINA1C, SERP1
GOTERM_ GO:0043413~biopolymer ST3GAL1, B4GALT1, ST6GAL1, STT3A, SERPINAIB, B3GALT1,
10 0,004028983 6,790653547 BP ALL glycosylation SERPINA1A, CES6, SERPINA1C, SERP1
GO:0044262~cellular B4GALT1, ST6GAL1, LDHA, B3GALT1, CES6, GNPNATl, PFKFB2,
GOTERM_
carbohydrate metabolic 21 0,009412614 HK2, CMAH, ACLY, ST3GAL1, ATF4, ISYNAl, STT3A, SERPINAIB, 15,18805686 BP_ALL
process SERPINA1A, SDS, SERPINA1C, GNMT, DCXR, SERP1
GOTER _ GO:0006487~protein amino
5 0,009845948 B4GALT1, STT3A, SERPINAIB, SERPINA1A, SERPINA1C 15,83200187 BP ALL acid N-linked glycosylation
GOTER _ GO:0009101~glycoprotein ST3GAL1, B4GALT1, ST6GAL1, STT3A, SERPINAIB, B3GALT1,
10 0,019531691 29,07781344 BP ALL biosynthetic process SERPINA1A, CES6, SERPINA1C, SERP1
GOTERM_ GO:0009100~glycoprotein ST3GAL1, B4GALT1, ST6GAL1, STT3A, SERPINAIB, B3GALT1,
10 0,067283126 70,27816604 BP ALL metabolic process SERPINA1A, CES6, SERPINA1C, SERP1
Annotation Enrichment Score:
Cluster 11 1.9456225560488778
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0045087~innate immune BCL10, IL1R1, CFB, C3, TIRAP, TLR2, C8A, C4BP, MYD88,
13 3,06E-04 0,530861442 BP ALL response LOC100048018, IL1RAP, CFH, LBP, MX2
GOTERM_ GO:0002250~adaptive C8A, ICAM1, BCL10, C4BP, MYD88, C3, CFB, RELB, GADD45G,
11 5,96E-04 1,032286375 BP ALL immune response BCL3, FAS
GO:0002460~adaptive
immune response based on
GOTERM_ somatic recombination of C8A, ICAM1, BCL10, C4BP, MYD88, C3, CFB, RELB, GADD45G,
11 5,96E-04 1,032286375 BP_ALL immune receptors built from BCL3, FAS
immunoglobulin superfamily
domains
C3, CSFl, TLR2, PAWR, MYD88, LOC100048018, CFH, LBP, FAS,
GOTER _ GO:0002682~regulation of THBS1, RUNX1, BCL10, HSP90AA1, LOC100045567, CFB, RELA,
23 0,00179026 3,073021395 BP_ALL immune system process SOCS5, C8A, ORM1, C4BP, LOC640441, RIPK2, RBM15, ORM2,
ORM3
GOTER _ GO:0002253~activation of C8A, BCL10, C4BP, MYD88, LOC100048018, C3, CFB, RELA,
10 0,002747438 4,679300509 BP ALL immune response TLR2, CFH, RIPK2
GO:0006957~complement
GOTER _
activation, alternative 4 0,004049216 C8A, LOC100048018, C3, CFB, CFH 6,823630831 BP ALL
pathway
GOTER _ GO:0002449~lymphocyte
9 0,004488951 C8A, ICAM1, BCL10, C4BP, MYD88, C3, CFB, BCL3, FAS 7,537644493 BP ALL mediated immunity
GOTERM_ GO:0019724~B cell mediated
8 0,00678231 C8A, BCL10, C4BP, YD88, C3, CFB, BCL3, FAS 11,17861848 BP ALL immunity
GO:0051605~protein
GOTERM_
maturation by peptide bond 8 0,00678231 C8A, C4BP, LOC100048018, C3, CFB, SPCS3, CFH, SPCS2, PCSK5 11,17861848 BP_ALL
cleavage
GO:0050778~positive
GOTERM_ BCL10, CFB, LOC100045567, C3, RELA, TLR2, C8A, MYD88,
regulation of immune 12 0,007282184 11,95408036 BP ALL C4BP, LOC100048O18, CFH, RIP 2, LBP
response
GOTERM_ GO:0006959~humoral
7 0,010250132 C8A, C4BP, LOC100048018, C3, CFB, CCR2, CFH, BCL3 16,42847333 BP ALL immune response
BCL10, C3, CFB, SOCS3, LOC100045567, RELA, TLR2, TIRAP,
GOTER _ GO:0048583~regulation of SOCS5, C8A, ADRB2, C4BP, MYD88, LOC640441,
21 0,010371682 16,60706833 BP ALL response to stimulus LOC100048018, HOPX, CFH, RIPK2, IL1B, LBP, THBS1, CPB2,
CBS
GOTERM_ GO:0002443~leukocyte
9 0,011441985 C8A, ICAM1, BCL10, C4BP, MYD88, C3, CFB, BCL3, FAS 18,1642263 BP ALL mediated immunity
GOTER _ GO:0002252~immune C8A, ICAMl, BCL10, C4BP, MY088, LOC100048018, C3, CFB,
11 0,011629328 18,43395262 BP ALL effector process CFH, BCL3, FAS, LBP
GO:0002684~positive BCL10, HSP90AA1, C3, LOC100045567, CFB, RELA, TLR2,
GOTER _
regulation of immune system 15 0,011905733 SOCS5, C8A, C4BP, MYD88, LOC640441, LOC100048018, CFH, 18,83037654 BP_ALL
process RIPK2, LBP, THBS1
GO:0048584~positive BCL10, C3, LOC100045567, CFB, RELA, TLR2, C8A, C4BP,
GOTERM_
regulation of response to 14 0,012158066 MYD88, LOC640441, LOC100048018, CFH, RIPK2, IL1B, LBP, 19,19068974 BP_ALL
stimulus THBS1
GOTERM_ GO:0080134~regulation of C3, LOC100045567, RELA, TIRAP, TLR2, ADRB2, MYD88,
14 0,013203149 20,66699885 BP ALL response to stress LOC100048018, HOPX, CFH, RIPK2, IL1B, LBP, CPB2, CBS
GOTERM_ GO:0016064~immunoglobulin
7 0,020860714 C8A, BCL10, C4BP, MYD88, C3, CFB, BCL3 30,73387105 BP ALL mediated immune response GO:0002455~humoral
GOTERM_
immune response mediated 5 0,031168668 C8A, C4BP, C3, CFB, BCL3 42,39522976 BP_ALL
by circulating immunoglobulin
GOTE M_ GO:0050776~regulation of BCL10, LOC100045567, CFB, C3, RELA, TLR2, SOCS5, C8A,
13 0,032564686 43,82409808 BP_ALL immune response C4BP, MYD88, LOC100048018, CFH, RIPK2, LBP
GO:0002541~activation of
GOTERM_
plasma proteins involved in 5 0,034143977 C8A, C4BP, LOC100048018, C3, CFB, CFH 45,40025836 BP_ALL
acute inflammatory response
GOTERM_ GO:0006956~complement
5 0,034143977 C8A, C4BP, LOC100048018, C3, CFB, CFH 45,40025836 BP ALL activation
GOTERM_ GO:0016485~protein
8 0,035260475 C8A, C4BP, LOC100048018, C3, CFB, SPCS3, CFH, SPCS2, PCSK5 46,48928968 BP ALL processing
GO:0031349~positive
GOTERM_
regulation of defense 6 0,045704139 MYD88, C3, RELA, TLR2, RIPK2, LBP 55,73086269 BP ALL
response
GOTER _ GO:0051604~protein
8 0,047361171 C8A, C4BP, LOC100048018, C3, CFB, SPCS3, CFH, SPCS2, PCSK5 57,05091097 BP ALL maturation
GOTERM_ GO:0031347~regulation of ADRB2, MYD88, LOC100048018, C3, RELA, TLR2, CFH, RIPK2,
8 0,064477752 68,6819415 BP ALL defense response LBP
GOTERM_ GO:00069S8~complement
4 0,082766838 C8A, C4BP, C3, CFB 77,79561417 BP ALL activation, classical pathway
GOTERM_ GO:0006518~peptide
3 0,377616752 SPCS3, SPCS2, PCSK5 99,97413475 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 12 1.832512148500975
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0030335~positive LOC100045000, LOC640441, CSFl, PTP4A1, TLR2, HBEGF,
6 0,008281886 13,48583023 BP ALL regulation of cell migration THBS1, CXCL10
GOTERM_ GO:00S1270~regulation of B4GALT1, LOC100045000, GTPBP4, LAMA3, LOC640441, CSFl,
10 0,011417265 18,12857417 BP ALL cell motion PTP4A1, CCR2, TLR2, HBEGF, THBS1, CXCL10
GOTERM_ GO:0051272~positive LOC100045000, LOC640441, CSFl, PTP4A1, TLR2, HBEGF,
6 0,012732541 20,00538069 BP ALL regulation of cell motion THBS1, CXCL10
GOTERM_ GO:0030334~regulation of LOC100045000, GTPBP4, LAMA3, LOC640441, CSFl, PTP4A1,
9 0,013803668 21,50376759 BP ALL cell migration CCR2, TLR2, HBEGF, THBS1, CXCL10
GOTERM_ GO:0040017~positive LOC100045000, LOC640441, CSFl, PTP4A1, TLR2, HBEGF,
6 0,016972935 25,78378323 BP ALL regulation of locomotion THBS1, CXCL10
GOTERM_ GO:0040012~regulation of LOC100045000, GTPBP4, LAMA3, LOC640441, CSFl, PTP4A1,
9 0,035856612 47,06234353 BP ALL locomotion CCR2, TLR2, HBEGF, THBS1, CXCL10
Annotation Enrichment Score:
Cluster 13 1.8291379882836822
Gene
Category Term PValue Genes FDR
Count
GGCT, LITAF, MCL1, LOC100044206, EGLN3, NFKB1, RFFL,
GOTERM_ PAWR, MAP3K5, CASP4, GATA6, BAG 3, KRT8, TRP53INP1,
GO:0006915~apoptosis 27 0,010424745 16,68492253 BP ALL ZC3H12A, FAS, BCL7C, TRAF3, BCL10, CLCA2, BIRC2, AHR,
BCL2L11, RASSF5, KRT18, SERPINA3G, GADD45G, RIPK2
GGCT, LITAF, MCL1, LOC100044206, EGLN3, NFKB1, RFFL,
GOTERM_ GO:0012501~programmed PAWR, MAP3K5, CASP4, GATA6, BAG3, KRT8, TRP53INP1,
27 0,012762838 20,04813112 BP ALL cell death ZC3H12A, FAS, BCL7C, TRAF3, BCL10, CLCA2, BIRC2, AHR,
BCL2L11, RASSF5, KRT18, SERPINA3G, GADD45G, RIPK2
GGCT, LITAF, MCL1, LOC100044206, EGLN3, NFKB1, RFFL,
GOTERM_ PAWR, MAP3K5, CASP4, GATA6, BAG3, KRT8, TRP53INP1,
GO:0008219~cell death 28 0,016846128 25,61684486 BP_ALL ZC3H12A, FAS, BCL7C, TRAF3, BCL10, CLCA2, BIRC2, AHR,
BCL2L11, C8A, RASSF5, KRT18, SERPINA3G, GADD45G, RIPK2
GGCT, LITAF, MCL1, LOC100044206, EGLN3, IMFKB1, RFFL,
GOTERM_ PAWR, IV1AP3K5, CASP4, GATA6, BAG3, KRT8, TRP53INP1,
GO:0016265~death 28 0,021524608 31,54741309 BP_ALL ZC3H12A, FAS, BCL7C, TRAF3, BCL10, CLCA2, BIRC2, AHR,
BCL2L11, C8A, RASSF5, KRT18, SERPINA3G, GADD45G, RIPK2
Annotation Enrichment Score:
Cluster 14 1.8244691455283093
Gene
Category Term PValue Genes FDR
Count
EGFR, GINS1, MAFF, FGFR1, CEBPB, GRB2, ELL, SOCS3, C6,
GOTERM_ GO:0001701~in utero
21 9,44E-04 TGFBRl, JUNB, BCL2L11, ACVR1B, SERPINA1B, GATA6, 1,631561776 BP_ALL embryonic development
SLC30A1, KRT8, HOPX, HBEGF, SKIL, RUNX1
FGFR1, GRB2, ELL, C6, ACVR1B, SERPINA1B, GATA6, SLC30A1,
GO:0009792~embryonic
GOTER _ KRT8, SKIL, ACSL4, RUNX1, PCSK5, EGFR, GINS1, MAFF, BCL10,
development ending in birth 26 0,006464962 10,68297523 BP_ALL CEBPB, SOCS3, TGFBRl, CELSRl, BCL2L11, BRCAl, JUNB, HOPX,
or egg hatching
HBEGF FGFR1, GRB2, ELL, C6, ACVR1B, SERPINA1B, GATA6, SLC30A1,
GOTERM_ GO:00 3009~chordate
25 0,010750707 KRT8, SKIL, RUNXl, PCSK5, EGFR, GINSl, MAFF, BCLIO, CEBPB, 17,161669 BP ALL embryonic development
SOCS3, TGFBRl, CELSRl, BCL2L11, BRCAl, JUNB, HOPX, HBEGF
FGFR1, EFNA1, GRB2, ELL, HMGCR, C6, LSR, ACVR1B,
SERPINA1B, GATA6, SLC30A1, KRT8, SKIL, ACSL4, RUNXl,
GOTERM_ GO:0009790~embryonic
32 0,055188902 PCSK5, GINSl, EGFR, MAFF, BCLIO, CEBPB, SOCS3, TGFBRl,
BP_ALL 62,80051195 development
SMADl, CELSRl, JUNB, BCL2L11, BRCAl, THBD, HOPX, HBEGF,
CML2
GOTERM_ GO:0048568~embryonic EGFR, FGFR1, CEBPB, GRB2, SOCS3, EFNA1, TGFBRl, KRT8,
12 0,208379215 98,29281018 BP ALL organ development CELSRl, RUNXl, PCSK5, JUNB
Annotation Enrichment Score:
Cluster 15 1.6993672079135298
Gene
Category Term PValue Genes FDR
Count
IFITM2, SKIV2L, IFITM3, TLR2, TIRAP, EDEM1, LEAP2, MYD88,
GOTERM_ GO:0009607~response to ISG15, KRT8, IFITM6, CREB3L2, ILIB, BCL3, LBP, STK19,
30 l,36E-06 0,002361348 BP_ALL biotic stimulus DNAJC3, MX2, BCLIO, PLD1, HSP90AA1, CFB, RELA,
1100001G20RIK, LCN2, PLSCR1, THBD, RIPK2, CD14, SERP1
GOTER _ GO:0002237~response to BCLIO, THBD, MYD88, RELA, TLR2, RIPK2, ILIB, LBP,
10 3.77E-05 0,065625806 BP_ALL molecule of bacterial origin 1100001G20RIK, CD14
GOTERM_ GO:0042035~regulation of INHBB, BCLIO, MYD88, CEBPB, REL, RELA, MAP2K3, BCL3, ILIB,
10 3,20E-04 0,555949997 BP_ALL cytokine biosynthetic process NFKB1
GOTERM_ GO:0070391~response to
4 3.84E-04 TLR2, RIPK2, LBP, CD14 0,666580683 BP_ALL lipoteichoic acid
GOTERM_ GO:0001817~regulation of BCLIO, CEBPB, RELA, MAP2K3, TLR2, NFKB1, INHBB, MYD88,
14 0,001010604 1,74583169 BP ALL cytokine production REL, ILIB, BCL3, RIPK2, LBP, CD14
GO:0032760~positive
GOTERM_
regulation of tumor necrosis 5 0,001394072 MYD88, TLR2, RIPK2, LBP, CD14 2,400725491 BP_ALL
factor production
BCLIO, PLD1, RELA, TLR2, TIRAP, 1100001G20RIK, LEAP2,
GOTERM_ GO:0051707~response to
19 0,001425598 LCN2, PLSCR1, MYD88, THBD, ISG15, KRT8, ILIB, RIPK2, BCL3, 2,45438332 BP_ALL other organism
LBP, MX2, CD14
A2 , TLR2, TIRAP, LEAP2, ARG1, MYD88, ISG15, KRT8, ILIB,
GOTERM_ GO:0051704~multi-organism BCL3, LBP, ACSL4, MX2, PCSK5, BCLIO, PLD1, RELA,
25 0,001444755 2,486974966 BP_ALL process 1100001G20RIK, JUNB, LCN2, PLSCR1, THBD, AVPR1A, RIPK2,
CD14
GOTERM_ GO:0032496~response to
7 0,001737037 THBD, MYD88, RIPK2, ILIB, LBP, 1100001G20RIK, CD14 2,982961647 BP_ALL lipopolysaccharide
GO:0032680~regulation of
GOTERM_
tumor necrosis factor 6 0,002032192 MYD88, TLR2, BCL3, RIPK2, LBP, CD14 3,481409012 BP_ALL
production
GOTERM_ GO:0002253~activation of C8A, BCLIO, C4BP, MYD88, LOC100048018, C3, CFB, RELA,
10 0,002747438 4,679300509 BP ALL immune response TLR2, CFH, RIPK2
GOTERM_ GO:0009617~response to BCLIO, PLD1, RELA, TIRAP, TLR2, 1100001G20RIK, LEAP2,
14 0,003018969 5,130377894 BP ALL bacterium MYD88, THBD, ILIB, BCL3, RIPK2, LBP, CD14
GO:0002221~pattern
GOTER _
recognition receptor signaling 4 0,004049216 MYD88, RELA, TLR2, RIPK2 6,823630831 BP_ALL
pathway
GOTERM_ GO:0032494~response to
4 0,005426645 MYD88, RELA, TLR2, RIPK2 9,043022208 BP ALL peptidoglycan
GO:0002758~innate immune
GOTER _
response-activating signal 4 0,007052583 MYD88, RELA, TLR2, RIPK2 11,59869335 BP_ALL
transduction
GO:0050830~defense
GOTERM_
response to Gram-positive 5 0,007274995 PLD1, MYD88, TLR2, RIPK2, LBP 11,94297378 BP ALL
bacterium
GO:0050778~positive
GOTERM_ BCLIO, CFB, LOC100045567, C3, RELA, TLR2, C8A, MYD88,
regulation of immune 12 0,007282184 11,95408036 BP_ALL C4BP, LOC100048018, CFH, RIPK2, LBP
response
GO:0051092~positive
GOTERM_
regulation of NF-kappaB 5 0,009845948 BCLIO, MYD88, RELA, TLR2, RIPK2 15,83200187 BP_ALL
transcription factor activity
GOTER _ GO:0002218~activation of
4 0,011087771 MYD88, RELA, TLR2, RIPK2 17,65194965 BP ALL innate immune response
GO:0002684~positive BCLIO, HSP90AA1, C3, LOC100045567, CFB, RELA, TLR2,
GOTERM_
regulation of immune system 15 0,011905733 SOCS5, C8A, C4BP, MYD88, LOC640441, LOC100048018, CFH, 18,83037654 BP_ALL
process RIPK2, LBP, THBS1
GO:0048584~positive BCLIO, C3, LOC100045567, CFB, RELA, TLR2, C8A, C4BP,
GOTERM_
regulation of response to 14 0,012158066 MYD88, LOC640441, LOC100048018, CFH, RIPK2, ILIB, LBP, 19,19068974 BP_ALL
stimulus THBS1
Figure imgf000088_0001
GOTERM_ GO:0009620~response to
3 0,114337291 BCLIO, MYD88, TLR2 87,9365032 BP ALL fungus
GOTERM_ GO:0080135~regulation of
6 0,115619248 MYD88, LOC100045567, TIRAP, RIPK2, ILIB, CBS 88,23707347 BP ALL cellular response to stress
GOTERM_ GO:0051090~regulation of
5 0,144615914 BCLIO, MYD88, RE LA, TLR2, RIPK2 93,41853399 BP ALL transcription factor activity
GOTERM_ GO:0042742~defense
7 0,16794766 PLD1, MYD88, TLR2, BCL3, RIPK2, LBP, LEAP2 95,93451195 BP ALL response to bacterium
GO:0009967~positive
GOTERM_ FGFRl, BCLIO, ADRB2, MYD88, LOC640441, LITAF, CSFl, RIPK2,
regulation of signal 9 0,240879151 99,17747564 BP ALL ILIB, THBS1
transduction
GOTERM_ GO:0051101~regulation of
5 0,250027223 BCLIO, MYD88, RELA, TLR2, RIPK2 99,33406632 BP ALL DNA binding
GO:0044093~positive
GOTERM_ BCLIO, KLK1B4, EFNA1, CSFl, RELA, MAP2K3, TIRAP, TLR2,
regulation of molecular 14 0,255290841 99,41095293 BP_ALL ADRB2, MAP3K5, MYD88, ANG, GADD45G, RIPK2
function
GO:0010647~positive
GOTERM_ FGFRl, BCLIO, ADRB2, MYD88, LOC640441, LITAF, CSFl, RIPK2,
regulation of cell 9 0,325374382 99,89469141 BP_ALL ILIB, THBS1
communication
GO:0002429~immune
GOTERM_ response-activating cell
3 0,414272211 BCLIO, TLR2, RIPK2 99,99101499 BP_ALL surface receptbf signaling
pathway
GOTERM_ GO.0045926~negative
4 0,443423638 ADRB2, MYD88, TLR2, SERTAD1 99,99630748 BP ALL regulation of growth
GO:0002768~immune
GOTERM_ response-regulating cell
3 0,449819175 BCLIO, TLR2, RIPK2 99,9969808 BP_ALL surface receptor signaling
pathway
Annotation Enrichment Score:
Cluster 16 1.571961501998509
Gene
Category Term PValue Genes FDR
Count
GO:0009070~serine family
GOTERM_
amino acid biosynthetic 4 0,001989401 CTH, PSPH, AGXT, CBS 3,409296261 BP ALL
process
GOTERM_ GO:0009069~serine family
4 0,038314846 CTH, PSPH, AGXT, CBS 49,36484908 BP ALL amino acid metabolic process
GOTERM_ GO:0008652~cellular amino
5 0,063686988 CTH, ASNS, PSPH, AGXT, CBS 68,21761447 BP ALL acid biosynthetic process
GOTERM_ GO:0009309~amine
6 0,106172924 CTH, HDC, ASNS, PSPH, AGXT, CBS 85,84564561 BP ALL biosynthetic process
Annotation Enrichment Score:
Cluster 17 1.4582578479364263
Gene
Category Term PValue Genes FDR
Count
GO:0051174~regulation of EGFR, BCLIO, GTPBP4, SOCS3, HMGCR, KLK1B4, EFNA1,
GOTERM_
phosphorus metabolic 21 0,003864712 MAP2K3, CSFl, TIRAP, RCAN1, MAP3K5, DUSP16, GADD45G, 6,52249971 BP_ALL
process ILIB, RAPGEF4, SPREDl, DNAJC3, GADD45A, PPP1R14A, CBS
EGFR, BCLIO, GTPBP4, SOCS3, HMGCR, KLK1B4, EFNA1,
GOTERM_ GO:0019220~regulation of
21 0,003864712 MAP2K3, CSFl, TIRAP, RCAN1, MAP3K5, DUSP16, GADD45G, 6,52249971 BP_ALL phosphate metabolic process
ILIB, RAPGEF4, SPREDl, DNAJC3, GADD45A, PPP1R14A, CBS
EGFR, BCLIO, GTPBP4, HMGCR, KLK1B4, EFNA1, SOCS3,
GOTERM_ GO:0042325~regulation of
20 0,00555548 MAP2K3, CSFl, TIRAP, MAP3K5, DUSP16, GADD45G, ILIB, 9,248039459 BP_ALL phosphorylation
RAPGEF4, SPREDl, DNAJC3, GADD45A, PPP1R14A, CBS
GTPBP4, HMGCR, KLK1B4, EFNA1, CSFl, MAP2K3, TIRAP,
GOTERM_ GO:0043549~regulation of
15 0,006627609 MAP3KS, DUSP16, GADD45G, ILIB, SPREDl, DIMAJC3, 10,93732628 BP_ALL kinase activity
GADD45A, CBS
GOTERM_ GO:0033673~negative
7 0,007789231 HMGCR, GADD45G, DUSP16, ILIB, SPREDl, DNAJC3, GADD45A 12,73414872 BP ALL regulation of kinase activity
GO:0006469~negative
GOTERM_
regulation of protein kinase 7 0,007789231 HMGCR, GADD45G, DUSP16, ILIB, SPREDl, DNAJC3, GADD45A 12,73414872 BP_ALL
activity
GOTERM_ GO:0043405~regulation of MAP3KS, HMGCR, EFNA1, MAP2K3, DUSP16, TIRAP, ILIB,
9 0,00818716 13,34177571 BP ALL MAP kinase activity SPREDl, CBS
GTPBP4, HMGCR, KLK1B4, EFNA1, CSFl, MAP2K3, TIRAP,
GOTERM_ GO:0051338~regulation of
15 0,008971526 MAP3K5, DUSP16, GADD45G, ILIB, SPREDl, DNAJC3, 14,52782239 BP ALL transferase activity
GADD45A, CBS
GO:0051348~negative
GOTERM_
regulation of transferase 7 0,009375927 HMGCR, GADD45G, DUSP16, ILIB, SPREDl, DNAJC3, GADD45A 15,13332726 BP ALL
activity GOTERM_ GO:0045859~regulation of GTPBP4, HMGCR, EFNAl, CSFl, MAP2K3, TIRAP, MAP3K5,
14 0,012158066 19,19068974 BP ALL protein kinase activity DUSP16, GADD45G, ILIB, SPREDl, DNAJC3, GADD45A, CBS
GO:0044092~negative
GOTER _ ADRB2, GTPBP4, HMGCR, GADD45G, DUSP16, ILIB, HSPA1A,
regulation of molecular 11 0,015729903 24,13201048 BP_ALL NOS3, HSPA1B, SPREDl, DNAJC3, GADD45A
function
GOTERM_ GO:0000165~MAPKKK MAP3K5, MYD88, GRB2, EFNAl, MAP2K3, GADD45G, DUSP16,
10 0,01675734 25,49974673 BP ALL cascade TIRAP, SPREDl, SMAD1
GOTERM_ GO:0043086~negative HMGCR, GADD45G, DUSP16, ILIB, HSPA1A, NOS3, HSPA1B,
9 0,023007193 33,33178949 BP ALL regulation of catalytic activity SPREDl, DNAJC3, GADD45A
GO:0043407~negative
GOTERM_
regulation of MAP kinase 4 0,029826226 HMGCR, DUSP16, ILIB, SPREDl 40,98894438 BP ALL
activity
KLK1B4, HMGCR, EFNAl, CSFl, TLR2, TIRAP, HSPA1A, HSPA1B,
GOTERM_ GO:0065009~regulation of MAP3K5, MYD88, ANG, DUSP16, ILIB, NOS3, SPREDl, DNAJC3,
25 0,127194036 90,64913349 BP_ALL molecular function BCLIO, GTPBP4, RELA, MAP2K3, RCAN1, ADRB2, GADD4SG,
RIPK2, GADD45A, CBS
FGFR1, LITAF, GRB2, HMGCR, EFNAl, CSFl, TIRAP, PAWR,
GOTERM_ GO:0009966~regulation of MAP3K5, MYD88, TIAM2, DUSP16, ILIB, RAPGEF4, SPREDl,
29 0,148461857 93,91538888 BP_ALL signal transduction SKIL, THBS1, FGD6, BCLIO, SOCS3, MAP2K3, SOCS5, FARP1,
CYP7B1, ADRB2, RGS1, LOC640441, RIPK2, WIF1, CBS
BCLIO, GTPBP4, HMGCR, KLK1B4, EFNAl, CSFl, MAP2K3,
GOTERM_ GO:0050790~regulation of TIRAP, HSPA1A, RCAN1, HSPA1B, ADRB2, MAP3K5, ANG,
21 0,172754247 96,32476583 BP ALL catalytic activity DUSP16, GADD45G, ILIB, NOS3, SPREDl, DNAJC3, GADD45A,
CBS
GOTERM_ GO:0000187~activation of
4 0,246448804 MAP3K5, EFNAl, MAP2K3, TIRAP 99,27649683 BP ALL MAP activity
GOTERM_ GO:0033674~positive
7 0,290027167 MAP3K5, KLK1B4, EFNAl, CSFl, MAP2K3, GADD45G, TIRAP 99,74367221 BP_ALL regulation of kinase activity
GO:0051347~positive
GOTERM_
regulation of transferase 7 0,32018446 MAP3K5, KLK1B4, EFNAl, CSFl, MAP2K3, GADD45G, TIRAP 99,87965214 BP_ALL
activity
GO:0043406~positive
GOTERM_
regulation of MAP kinase 4 0,331292932 MAP3K5, EFNAl, MAP2K3, TIRAP 99,909676 BP ALL
activity
GO:0045860~positive
GOTERM_
regulation of protein kinase 6 0,423763113 MAP3K5, EFNAl, CSFl, MAP2K3, GADD45G, TIRAP 99,99324017 BP_ALL
activity
GOTERM_ GO:0043085~positive BCLIO, ADRB2, MAP3K5, KLK1B4, ANG, EFNAl, CSFl, MAP2K3,
10 0,544609163 99,99988794 BP ALL regulation of catalytic activity GADD45G, TIRAP
Annotation Enrichment Score:
Cluster 18 1.403300854158408
Gene
Category Term PValue Genes FDR
Count
LDHA, GNPNAT1, PFKFB2, HK2, ST3GAL1, ISYNAl, STT3A,
SERPINAIB, ITIH1, SERPINA1A, SERPINA1C, ITIH4, ITIH2,
GOTERM_ GO:0005975~carbohydrate
30 0,001042317 GNMT, ITIH3, B4GALT1, ST6GAL1, B3GALT1, CES6, CMAH, 1,800148358 BP_ALL metabolic process
CHI3L3, ACLY, CHI3L4, SLC3A1, ATF4, CHID1, SDS, GFPT1,
DCXR, SERPl
GO:0044262~cellular B4GALT1, ST6GAL1, LDHA, B3GALT1, CES6, GNPNAT1, PFKFB2,
GOTERM_
carbohydrate metabolic 21 0,009412614 HK2, CMAH, ACLY, ST3GAL1, ATF4, ISYNAl, STT3A, SERPINAIB, 15,18805686 BP_ALL
process SERPINA1A, SDS, SERPINA1C, GNMT, DCXR, SERPl
GOTERM_ GO:0005996~monosaccharide B4GALT1, ATF4, LDHA, SDS, GNPNAT1, PFKFB2, HK2, CMAH,
11 0,12335165 89,90556228 BP ALL metabolic process GNMT, DCXR, SERPl
GOTERM_ GO:0019318~hexose
9 0,226783926 B4GALT1, ATF4, LDHA, SDS, PFKFB2, HK2, GNMT, DCXR, SERPl 98,8667521 BP ALL metabolic process
GOTERM_ GO:0006006~glucose
7 0,350774756 ATF4, LDHA, SDS, HK2, GNMT, DCXR, SERPl 99,94603209 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 19 1.3347090707323013
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0030212~hyaluronan
4 0,001275865 ITIH1, ITIH4, ITIH2, ITIH3 2,199289318 BP ALL metabolic process
GOTERM_ GO:0006022~aminoglycan
7 0,008556247 CHID1, ITIH1, ITIH4, ITIH2, CHI3L3, ITIH3, CHI3L4 13,90179419 BP ALL metabolic process
GOTERM_ GO:0005976~polysaccharide
8 0,0390371 CHID1, ITIH1, ITIH4, ITIH2, CHI3L3, GNMT, ITIH3, CHI3L4 50,02319443 BP ALL metabolic process
GOTERM_ GO:0006032~chitin catabolic
3 0,044237908 CHID1, CHI3L3, CHI3L4 54,53101077 BP ALL process
GOTERM_ GO:0006030~chitin metabolic
3 0,052862633 CHID1, CHI3L3, CHI3L4 61,17244213 BP ALL process GOTERIVL GO:0006026~aminoglycan
3 0,125822558 CHID1, CHI3L3, CHI3L4 90,38986191 BP_ALL catabolic process
GOTERM_ GO:0030203~glycosaminoglyc
4 0,157752081 ITIH1, ITIH4, ITIH2, ITIH3 94,97372269 BP ALL an metabolic process
GOTERM_ GO:0000272~polysaccharide
3 0,161706513 CHID1, CHI3L3, CHI3L4 95,36932009 BP ALL catabolic process
GOTERM_ GO:0016052~carbohydrate
5 0,30384239 LDHA, CHID1, HK2, CHI3L3, CHI3L4 99,81797118 BP ALL catabolic process
Annotation Enrichment Score:
Cluster 20 1.3105571046825986
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006882~cellular zinc ion
4 0,001275865 SLC30A1, MT2, MTl, SLC39A4 2,199289318 BP ALL homeostasis
GOTERM„ GO:0055069~zinc ion
4 0,001989401 SLC30A1, MT2, MTl, SLC39A4 3,409296261 BP ALL homeostasis
CCL2, FOXA3, CSF1, PRDX4, PDIA6, HSPA1A, PDIA5, HSPA1B,
PDIA4, TIMP1, SLC11A2, ALAS2, SLC30A1, MT2, ILIB, MTl,
GOTERM_ GO:0042592~homeostatic
32 0,011322779 FBX04, FAS, SKIL, SLC39A4, QSOX1, SCD2, ATP4A, SMAD1, 17,99216354 BP_ALL process
SLC9A3R1, BCL2L11, STAT3, ADRB2, ATP2A2, NUCB2, AVPRIA,
NR5A2, SCARA5
GOTERM_ GO:0055066~di-, tri-valent SLC11A2, ALAS2, CCL2, ATP2A2, SLC30A1, NUCB2, AVPRIA,
12 0,012080954
BP ALL 19,08073898 inorganic cation homeostasis MT2, MTl, ILIB, SLC39A4, SCARA5
GO:0030005~cellular di-, tri-
GOTERM ALAS2, CCL2, ATP2A2, SLC30A1, NUCB2, AVPRIA, MT2, MTl,
valent inorganic cation 11 0,0173104 26,22633034 BP_ALL ILIB, SLC39A4, SCARA5
homeostasis
GOTERM_ GO:0055080~cation CCL2, ATP4A, SLC11A2, ALAS2, ATP2A2, SLC30A1, NUCB2,
13 0,025360059 36,07387183 BP ALL homeostasis MT2, AVPRIA, ILIB, MTl, SLC39A4, SCARA5
FOXA3, F13A1, FERMT2, PRDX4, PDIA6, PDIA5, PDIA4, ALAS2,
SERPINA6, PROZ, MT2, MTl, ILIB, NOS3, RAPGEF4, FAS,
SERTAD1, GTPBP4, F10, ATP4A, SOCS5, TACC3, SLC9A3R1,
GOTERM_ GO:0065008~regulation of
51 0,034237402 BCL2L11, ADRB2, THBD, NUCB2, UNC13B, CCL2, RBP1, CSF1, 45,49218063 BP_ALL biological quality
HSPA1A, HSPA1B, TIMP1, SLC11A2, FGA, SLC30A1, FBX04,
SKIL, SLC39A4, PCSK5, QSOX1, FN1, SCD2, IL1RN, SMAD1,
STAT3, CYP17A1, ATP2A2, AVPRIA, NR5A2, SCARA5
GOTERM_ GO:0030003~cellular cation ALAS2, CCL2, ATP2A2, SLC30A1, NUCB2, AVPRIA, MT2, MTl,
11 0,037186812 48,32025097 BP ALL homeostasis ILIB, SLC39A4, SCARA5
SCD2, CCL2, FOXA3, PRDX4, PDIA6, PDIA5, PDIA4, SLC9A3R1,
GOTERM_ GO:0019725~cellular
19 0,050026222 ALAS2, ATP2A2, SLC30A1, NUCB2, AVPRIA, MT2, MTl, ILIB, 59,09644444 BP_ALL homeostasis
SLC39A4, QSOX1, SCARA5
SCD2, CCL2, ATP4A, FOXA3, SLC9A3R1, STAT3, SLC11A2,
GOTERM_ GO:0048878~chemical
18 0,126986995 ALAS2, ATP2A2, SLC30A1, NUCB2, AVPRIA, MT2, MTl, ILIB, 90,61042059 BP_ALL homeostasis
SLC39A4, NR5A2, SCARA5
GOTERM_ GO:0055082~cellular SCD2, CCL2, FOXA3, SLC9A3R1, ALAS2, ATP2A2, SLC30A1,
14 0,134358705 91,89978094 BP ALL chemical homeostasis NUCB2, MT2, AVPRIA, ILIB, MTl, SLC39A4, SCARA5
GOTERM_ SCD2, CCL2, ATP4A, SLC9A3R1, SLC11A2, ALAS2, ATP2A2,
GO:0050801~ion homeostasis 15 0,134729192 91,9599574 BP ALL SLC30A1, NUCB2, MT2, AVPRIA, ILIB, MTl, SLC39A4, SCARA5
GOTERM_ GO:0006873~cellular ion CCL2, SCD2, SLC9A3R1, ALAS2, ATP2A2, SLC30A1, NUCB2,
13 0,189825692 97,44413365 BP_ALL homeostasis MT2, AVPRIA, ILIB, MTl, SLC39A4, SCARAS
GOTERM_ GO:0006875~cellular metal
6 0,260827725 CCL2, ATP2A2, NUCB2, AVPRIA, MTl, ILIB 99,48275665 BP ALL ion homeostasis
GOTERM_ GO:0055065~metal ion
6 0,300755399 CCL2, ATP2A2, NUCB2, AVPRIA, MTl, ILIB 99,80338739 BP ALL homeostasis
GOTERM_ GO:0006874~cellular calcium
5 0,382323043 CCL2, ATP2A2, NUCB2, AVPRIA, ILIB 99,97733815 BP ALL ion homeostasis
GOTERM_ GO:0055074~calcium ion
5 0,413583894 CCL2, ATP2A2, NUCB2, AVPRIA, ILIB 99,99082928 BP ALL homeostasis
Annotation Enrichment Score:
Cluster 21 1.2951798564014225
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0046700~heterocycle
7 0,004677505 TD02, ALDH1L1, LOC100045567, HDC, HAL, MOXD1, AFMID 7,842222898 BP_ALL catabolic process
GOTERM_ GO:0046395~carboxylic acid ACOX2, HACL1, TD02, HDC, HAL, AKR1D1, TAT, MOXD1,
9 0,006601522 10,896577 BP ALL catabolic process AFMID
GOTERM_ GO:0016054~organic acid ACOX2, HACL1, TD02, HDC, HAL, AKR1D1, TAT, MOXD1,
9 0,006601522 10,896577 BP ALL catabolic process AFMID
GOTERM_ GO:0019439~aromatic
4 0,013511196 TD02, ALDH1L1, TAT, AFMID 21,09727904 BP ALL compound catabolic process GOTERM_ GO:0009063~cellular amino
6 0,037484372 TD02, HDC, HAL, TAT, MOXD1, AFMID 48,5977571 BP ALL acid catabolic process
GOTERM_ GO:0006548~histidine
3 0,052862633 HDC, HAL, MOXD1 61,17244213 BP ALL catabolic process
GOTERM_ GO:0006547~histidine
3 0,052862633 HDC, HAL, MOXD1 61,17244213 BP ALL metabolic process
GOTERM_ GO:0009077~histidine family
3 0,052862633 HDC, HAL, MOXD1 61,17244213 BP ALL amino acid catabolic process
GOTERM_ GO:0009074~aromatic amino
3 0,052862633 TD02, TAT, AFMID 61,17244213 BP ALL acid family catabolic process
GOTER _ GO:0009075~histidine family
3 0,052862633 HDC, HAL, MOXD1 61,17244213 BP_ALL amino acid metabolic process
GOTERM_ GO:0009310~amine catabolic
6 0,072478673 TD02, HDC, HAL, TAT, MOXD1, AFMID 73,03387138 BP ALL process
GOTERM_ GO:0009072~aromatic amino
3 0,161706513 TD02, TAT, AFMID 95,36932009 BP ALL acid family metabolic process
GO:0006725~cellular
GOTERM_
aromatic compound 7 0,198950956 TD02, ALDH1L1, HDC, GNMT, TAT, MOXD1, AFMID 97,90179303 BP_ALL
metabolic process
GOTER _ GO:0006576~biogenic amine
4 0,522521196 TD02, HDC, MOXD1, AFMID 99.9997443 BP ALL metabolic process
GO:0006575~cellular amino
GOTERM_
acid derivative metabolic 5 0,719323228 TD02, HDC, GNMT, MOXD1, AFMID 99,99999998 BP__ALL
process
Annotation Enrichment Score:
Cluster 22 1.1855520945337523
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0001942~hair follicle
6 0,028040621 EGFR, ACVR1B, FOXQ1, RELA, FST, SOX9 39,06822299 BP_ALL development
GOTERM_ GO:0022404~molting cycle
6 0,028040621 EGFR, ACVR1B, FOXQ1, RELA, FST, SOX9 39,06822299 BP ALL process
GOTERM_ GO:0022405~hair cycle
6 0,028040621 EGFR, ACVR1B, FOXQ1, RELA, FST, SOX9 39,06822299 BP ALL process
GOTERM_
GO:0042303~molting cycle 6 0,032548838 EGFR, ACVR1B, FOXQ1, RELA, FST, SOX9 43,80806693 BP ALL
GOTERM_
GO:0042633~hair cycle 6 0,032548838 EGFR, ACVR1B, FOXQ1, RELA, FST, SOX9 43,80806693 BP ALL
GOTERM_ GO:0008544~epidermis
8 0,139582117 EGFR, ACVR1B, FOXQ1, PPL, RELA, TGM1, FST, SOX9 92,71028509 BP ALL development
GOTERM_ GO:0007398~ectoderm
8 0,174322129 EGFR, ACVR1B, FOXQ1, PPL, RELA, TGM1, FST, SOX9 96,44423079 BP ALL development
GOTERM_ GO:0048729~tissue EGFR, BCL10, CYP7B1, FOXQ1, CSF1, FST, CELSRl, SMAD1,
9 0,576722756 99,99996865 BP ALL morphogenesis SOX9
Annotation Enrichment Score:
Cluster 23 1.1303708760489908
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009991~response to FOS, PPAN, LDHA, FOXA3, CFB, SKIV2L, AVPRIA, CP, RUNXl,
11 0,016506138 25,16750649 BP ALL extracellular stimulus STK19, CBS
GOTERM_ GO:0007584~response to
6 0,120487774 CFB, SKIV2L, CP, RUNXl, STK19, CBS 89,31547253 BP ALL nutrient
GOTER _ GO:0031667~response to
7 0,204314377 FOXA3, CFB, SKIV2L, CP, RUNXl, STK19, CBS 98,13350407 BP ALL nutrient levels
Annotation Enrichment Score:
Cluster 24 1.0381130241170293
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0001568~blood vessel B4GALT1, FGFRl, SOCS3, TGFBRl, TIPARP, MMP19, JUNB,
14 0,078550116 75,94880258 BP ALL development ANG, DHCR7, ZC3H12A, HBEGF, ILIB, NOS3, RBM15
GOTERM_ GO:0048514~blood vessel B4GALT1, FGFRl, ANG, TGFBRl, TIPARP, MMP19, ILIB, HBEGF,
12 0,080457819 76,80157036 BP ALL morphogenesis ZC3H12A, NOS3, RBM15, JUNB
GOTERM_ B4GALT1, FGFRl, ANG, MMP19, ILIB, HBEGF, ZC3H12A, NOS3,
GO:0001525~angiogenesis 9 0,088176549 79,96959219 BP ALL RBM15
GOTERM_ GO:0001944~vasculature B4GALT1, FGFRl, SOCS3, TGFBRl, TIPARP, MMP19, JUNB,
14 0,091118685 81,06606245 BP ALL development ANG, DHCR7, ZC3H12A, HBEGF, ILIB, NOS3, RBM15
GO:0048646~anatomical B4GALT1, BCL10, FGFRl, GRB2, EFNA1, MMP19, SMAD1,
GOTERM_
structure formation involved 18 0,126986995 CELSRl, JUNB, BCL2L11, ANG, HOPX, ILIB, ZC3H12A, HBEGF, 90,61042059 BP_ALL
in morphogenesis NOS3, SKIL, RBM15 Annotation Enrichment Score:
Cluster 25 1.0242333448202474
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0030155~regulation of ICAMl, SM0C2, GTPBP4, LAMA3, LOC640441, CSFl, VTN,
8 0,04306917 53,55271883 BP_ALL cell adhesion THBS1, CML2
GO:0010811~positive
GOTERM_
regulation of cell-substrate 4 0,064229433 SMOC2, LOC640441, CSFl, VTN, THBS1 68,53682489 BP_ALL
adhesion
GOTERM_ GO:0010810~regulation of
4 0,157752081 SMOC2, LOC640441, CSFl, VTN, THBS1 94,97372269 BP ALL cell-substrate adhesion
GOTERM_ GO:0045785~positive
4 0,183312016 SMOC2, LOC640441, CSFl, VTN, THBS1 97,06156691 BP_ALL regulation of cell adhesion
Annotation Enrichment Score:
Cluster 26 1.0170180726661258
Gene
Category Term PValue Genes FDR
Count
GOTERM_
GO:0060326~cell chemotaxis 5 0,012942807 CCRl, S100A9, IL1B, CSF3R, LBP 20,3016295 BP ALL
GOTERM_ GO:0030595~leukocyte
5 0,012942807 CCRl, S100A9, IL1B, CSF3R, LBP 20,3016295 BP ALL chemotaxis
GOTERM_ GO:0050900~leukocyte
6 0,015468541 B4GALT1, CCRl, S100A9, IL1B, CSF3R, LBP 23,78032547 BP ALL migration
EGFR, B4GALT1, PVR, CCL2, CXCL5, S100A8, CCRl, TGFBRl,
GOTERM_
GO:0040011~locomotion 20 0,047450436 S100A9, CCL9, CCL19, CXCLll, CCL6, CXCLIO, LOC100045000, 57,12095809 BP_ALL
TNSl, CXCL13, IL1B, CSF3R, HBEGF, LBP
GOTERM_ EGFR, B4GALT1, PVR, TNSl, TGFBRl, CCRl, S100A9, IL1B,
GO.0016477~cell migration 11 0,311880949 99,85131082 BP ALL CSF3R, HBEGF, LBP
GOTERM_ EGFR, B4GALT1, PVR, TNSl, TGFBRl, CCRl, S100A9, IL1B,
GO:0048870~cell motility 11 0,513841936 99,99965005 BP ALL CSF3R, HBEGF, LBP
GOTERM GO:0051674~localization of EGFR, B4GALT1, PVR, TNSl, TGFBRl, CCRl, S100A9, IL1B,
11 0,513841936 99,99965005 BP ALL cell CSF3R, HBEGF, LBP
GOTERM_ ALCAM, EGFR, B4GALT1, PVR, TNSl, TGFBRl, CCRl, S100A9,
GO:0006928~cell motion 12 0,72187331 99,99999998 BP_ALL IL1B, CSF3R, HBEGF, LBP
Annotation Enrichment Score:
Cluster 27 1.0094962939601124
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0046688~response to
3 0,022098824 LCAT, MT2, MT1 32,24379101 BP ALL copper ion
GOTERM_ GO:0010038~response to
5 0,108616797 SLC11A2, LCAT, MT2, MT1, TAT 86,50484252 BP ALL metal ion
GOTERM_ GO:0010035~response to
5 0,390162 SLC11A2, LCAT, MT2, MT1, TAT 99,98185846 BP_ALL inorganic substance
Annotation Enrichment Score:
Cluster 28 0.9922981670864653
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0042093~T-helper cell
3 0,011015655 RELB, GADD45G, BCL3 17,54728222 BP ALL differentiation
GO:0002294~CD4-positive,
GOTERM_ alpha-beta T cell
3 0,011015655 RELB, GADD45G, BCL3 17,54728222 BP_ALL differentiation during
immune response
GO:0002292~T cell
GOTERM_
differentiation during 3 0,016149407 RELB, GADD45G, BCL3 24,69329358 BP ALL
immune response
GO:0002293~alpha-beta T cell
GOTERM_
differentiation during 3 0,016149407 RELB, GADD45G, BCL3 24,69329358 BP_ALL
immune response
GO:0002287~alpha-beta T cell
GOTERM_
activation during immune 3 0,022098824 RELB, GADD45G, BCL3 32,24379101 BP_ALL
response
GOTERM_ GO:0042088~T-helper 1 type
3 0,028801965 RELB, GADD45G, BCL3 39,89427383 BP ALL immune response
GO:0043367~CD4-positive,
GOTERM_
alpha beta T cell 3 0,044237908 RELB, GADD45G, BCL3 54,53101077 BP_ALL
differentiation GOTER _ GO:0002286~T cell activation
3 0,081775145 RELB, GADD45G, BCL3 77,37370798 BP ALL during immune response
GOTER _ GO:0002263~cell activation
4 0,089401663 RELB, GADD45G, BCL3, LBP 80,43324447 BP ALL during immune response
GO:0002366~leukocyte
GOTER _
activation during immune 4 0,089401663 RELB, GADD45G, BCL3, LBP 80,43324447 BP_ALL
response
GOTERM_ GO:0046632~alpha-beta T cell
3 0,137566392 RELB, GADD45G, BCL3 92,40701766 BP ALL differentiation
GO:0002285~lymphocyte
GOTERM_
activation during immune 3 0,137566392 RELB, GADD45G, BCL3 92,40701766 BP ALL
response
GOTER _ GO:0046631~alpha-beta T cell
3 0,186528999 RELB, GADD45G, BCL3 97,25679507 BP ALL activation
GOTER _ GO:0030217~T cell
5 0,265216822 EGR1, RELB, GADD45G, BCL3, FAS 99,5337256 BP ALL differentiation
GOTERM_
GO:0042110~T cell activation 6 0,368979942 EGR1, RELB, GADD45G, BCL3, RIPK2, FAS 99,96711685 BP ALL
GOTERM_ EGR1, BCL10, FGA, RELB, GADD45G, BCL3, RIP 2, FAS, LBP,
GO:0001775~cell activation 10 0,471743751 99,99851317 BP ALL TIMP1
GOTERM_ GO:0002521~leukocyte
6 0,542382267 EGR1, RELB, GADD45G, CD300LF, BCL3, FAS 99,99987801 BP ALL differentiation
GOTERM_ GO:0030098~lymphocyte
5 0,554787512 EGR1, RELB, GADD45G, BCL3, FAS 99,99992442 BP ALL differentiation
GOTERM_ GO:0045321~leukocyte
8 0,631398525 EGR1, BCL10, RELB, GADD45G, BCL3, RIPK2, FAS, LBP 99,99999718 BP ALL activation
GOTER _ GO:0046649~lymphocyte
6 0,790656332 EGR1, RELB, GADD45G, BCL3, RIPK2, FAS 100 BP ALL activation
Annotation Enrichment Score:
Cluster 29 0.9790722741201915
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0070167~regulation of
3 0,103143792 ANK, ADRB2, SOX9 84,98643396 BP ALL biomineral formation
GOTERM_ GO:0030500~regulation of
3 0,103143792 ANK, ADRB2, SOX9 84,98643396 BP ALL bone mineralization
GOTERM_ GO:0030278~regulation of
5 0,108616797 ANK, ADRB2, CSF1, SMAD1, SOX9 86,50484252 BP ALL ossification
Annotation Enrichment Score:
Cluster 30 0.9766492347958228
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0001890~placenta
8 0,030062957 EGFR, CEBPB, GRB2, SOCS3, KRT8, BIRC2, RBM15, JUNB 41,23926138 BP ALL development
GOTERM_ GO:0001892~embryonic
6 0,058208059 EGFR, CEBPB, GRB2, SOCS3, KRT8, JUNB 64,81768442 BP ALL placenta development
GOTER _ GO:0048568~embryonic EGFR, FGFR1, CEBPB, GRB2, SOCS3, EFNA1, TGFBR1, KRT8,
12 0,208379215 98,29281018 BP ALL organ development CELSRl, RUNX1, PCSK5, JUNB
GOTER _ GO:0060711~labyrinthine
3 0,340043004 GRB2, SOCS3, JUNB 99,92819375 BP ALL layer development
Annotation Enrichment Score:
Cluster 31 0.9594682580007974
Gene
Category Term PValue Genes FDR
Count
C3, GLUDl, CSF1, TLR2, CXCL10, LOC100045000, ANG, ILIB,
GOTERM_ GO:0032879~regulation of YRDC, NOS3, RAPGEF4, NEDD4L, THBS1, B4GALT1, GTPBP4,
25 0,00716935 11,77959914 BP_ALL localization ATP4A, CELSRl, TACC3, INHBB, ADRB2, LAMA3, LOC640441,
GRM8, PTP4A1, CCR2, HBEGF, SERP1
GOTERM_ GO:0051046~regulation of INHBB, B4GALT1, GRM8, ANG, GLUDl, ILIB, RAPGEF4, CELSRl,
9 0,066631533 69,91440582 BP ALL secretion SERP1
GOTERM_ GO:0051049~regulation of B4GALT1, ATP4A, C3, GLUDl, CELSRl, TACC3, INHBB, ADRB2,
16 0,069398821 71,4309055 BP ALL transport GR 8, ANG, ILIB, RAPGEF4, NOS3, YRDC, NEDD4L, SERP1
GO:0046887~positive
GOTERM_
regulation of hormone 3 0,081775145 INHBB, GLUDl, SERP1 77,37370798 BP_ALL
secretion
GOTERM_ GO:0060341~regulation of INHBB, B4GALT1, GRM8, ANG, GLUDl, ILIB, RAPGEF4, CELSRl,
10 0,10385141 85,19144138 BP ALL cellular localization TACC3, SERP1
GOTERM_ GO:0046883~regulation of
4 0,125627213 INHBB, GLUDl, ILIB, SERP1 90,35238614 BP ALL hormone secretion GOTERM_ GO:0050796~regulation of
3 0,174045679 INHBB, GLUD1, SERPl 96,423436 BP ALL insulin secretion
GOTERM_ GO:0002791~regulation of
3 0,224606914 INHBB, GLUD1, SERPl 98,80987037 BP ALL peptide secretion
GOTERM_ GO:0051047~positive
4 0,274487072 INHBB, ANG, GLUD1, SERPl 99,62623989 BP ALL regulation of secretion
GOTERM_ GO:0051050~positive
5 0,670008086 INHBB, C3, ANG, GLUD1, SERPl 99,99999959 BP ALL regulation of transport
Annotation Enrichment Score:
Cluster 32 0.9411922393677707
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0042278~purine
4 0,04789565 HMGCR, LOC100045567, ADK, GNMT 57,46871986 BP ALL nucleoside metabolic process
GO:0046128~purine
GOTER _
ribonucleoside metabolic 4 0,04789565 H GCR, LOC100045567, ADK, GNMT 57,46871986 BP_ALL
process
GOTERM_ GO:0009116~nucleoside
5 0,126070417 PNP2, HMGCR, LOC100045567, ADK, GNMT 90,43721467 BP_ALL metabolic process
GOTERM_ GO:0009119~ribpnucleoside
4 0,149493899 HMGCR, LOC100045567, ADK, GNMT 94,04257252 BP_ALL metabolic process
GO:0055086~nucleobase,
GOTERM_ ATP2A2, ATP4A, PNP2, HMGCR, LOC100045567, ADK, ATP11A,
nucleoside and nucleotide 11 0,455208115 99,99745651 BP_ALL KMO, GNMT, GUCY2C, DCXR
metabolic process
Annotation Enrichment Score:
Cluster 33 0.9349014641649622
Gene
Category Term PValue Genes FDR
Count
LDHA, LOC100044206, KLK1B4, EFNA1, SYNCRIP, MAP3K5,
EROILB, MYD88, DNAJB11, ISG15, APOF, SULT1A1, I TS7,
CH25H, LCAT, MAP3K8, CREB3L2, CFH, RPL12, FAS, ADAM9,
PLD1, F10, CYP3A13, EMG1, YY1, PIM1, PIM3, LOC100044878,
ADAMTS4, RAD23B, HACL1, RBP1, ELL, ZFP612, PFKFB2,
ENPP3, HSPA1A, RFFL, HSPA1B, SLC11A2, ARG1, SERPINA1B,
SERPINA1A, SERPINA1C, DUSP16, FBX04, PABPC1,
LOC100043996, IKZF4, ST6GAL1, SCD2, SUB1, OSBPL9, CFB,
MAP2K3, TGFBR1, IL1RN, ATP11A, UBE2L6, TREX1, CHI3L3,
CHI3L4, SMAD1, GUCY2C, HNRNPA1, PTPN12, PPA1, CYP7B1,
CYP17A1, ATP2A2, HOPX, PPRC1, IDI1, CML2, BACH1, STEAP4,
FOXA3, GAR1, GNPNAT1, NFKB1, PMVK, PTER, HSPH1, RRP1B,
SAA1, SERPINA6, IL1RAP, NOS3, SIK1, SERTAD1, NFKBIZ,
ATP4A, LPGATl, CAR 14, ACNAT2, MMP19, TLE3, TLEl, SLC3A1,
EIF1A, RAD52, GTF2B, MBD1, RDH5, C8A, SQLE, SDS, ADK,
GADD45G, RBM39, FKBPll, SERPl, HSD3B2, HSD3B3, HSD3B6,
HSD17B2, C3, PRTN3, CREM, HSD3B5, HK2, EDEM1, PCOLCE,
RPL30, STT3A, XBPl, LOC100046232, DHCR7, ALOX5AP, PREPL,
BCL3, ETV6, ACSL4, QSOX1, PCSK5, RBM25, TMPRSS2, CES6,
GOTERM_ GO:0008152~metabolic
280 3,17E-04 CAPN8, CYP4F14, SPSB4, ACLY, STAT3, PAPOLA, GFPT1, 0,550415734 BP_ALL process
PTP4A1, CYP4F15, AOX3, CP, CWC22, NR5A2, APOBEC1,
ALDH1L1, HMGCR, F13A1, SNRPD3, MMP8, TIRAP, CNOT7,
AGXT, FDFTl, ST3GAL1, LOC100048018, GATA6, ELOVL3, CLPl,
BC089597, 2010111I01RIK, EGFR, SOCS3, RE LA, RE LB, PRKAB1,
HAL, CMAH, HES6, SOCS5, GRHL1, TAT, JUNB, MOXD1, AHR,
RCL1, C4BP, CHID1, RIPK2, DNTTIP2, SRXN1, FGFR1, CYP2C44,
MVD, LITAF, GLUD1, KMO, ABCA1, SOX9, RIOK2, MED12L,
FOXQ1, ISYNA1, RPL3, GNMT, LYSMD2, RUNX1, B4GALT1,
GINS1, MAFF, CSTF3, PTPN2, LOC100045567, CYB561, BRCA1,
UGT2B38, UGT2B37, IKBKE, ATF4, PPID, SPCS3, HIVEP2,
DNAJB1, PTPN1, SPCS2, DNAJB4, CPB2, DCXR, ACOX2,
METAP1, DPH5, PRDX4, HP, LSS, PAWR, PSPH, AFMID,
SC4MOL, ACVR1B, TD02, ALAS2, CASP4, ITIH1, ANG, HDC,
PROZ, ITIH4, ITIH2, ITIH3, NFIL3, MKL1, ZCCHC6, EGR1,
HSP90AA1, ARID5A, TARS, CTH, BTG2, CTSC, AKR1D1,
CAMK1D, CYP51, FKBP5, PNP2, TIPARP, UTP6, TRA2A, EGLN3,
ASNS, NFYB, REL, ADH4, TGM1, NEDD4L, B4GALNT1, CYP2C70,
CEBPB, CEBPD, B3GALT1, SDSL, IRF9, WSB1, SLC35C1, IRF5,
DR1, SDR42E1, CBS S100A6, LOC100044206, ARCKSL1, KLK1B4, FST, TLR2,
NFKB1, VTN, PAWR, CNOT7, CXCL10, FOS, CASP4, MYD88,
LOC100048018, ANG, GATA6, CFH, IL1B, NOS3, FAS, YAPl, LBP,
MKL1, SERTAD1, ADA 9, EGR1, EGFR, BCL10, HSP90AA1,
GO:0048518~positive SOCS3, RELA, LIFR, SOCS5, JUNB, AHR, BCL2L11, INHBB, C8A,
GOTER _
regulation of biological 75 7,62E-04 ADRB2, C4BP, LOC640441, RIPK2, SERP1, FGFR1, CCL2, LITAF, 1,318292002 BP_ALL
process C3, CSF1, GLUD1, BEX1, NFYB, SOX9, LOC1D0045000, SMOC2,
REL, BCL3, TRP53INP1, FBX04, RUNX1, THBS1, SYNPO,
B4GALT1, CEBPB, CFB, LOC100045567, CEBPD, TGFBR1,
SMAD1, BRCA1, STAT3, CYP7B1, ATF4, PTP4A1, HOPX, HBEGF,
NR5A2, RBM15, CD14
LDHA, LOC100044206, KLK1B4, EFIMA1, SYNCRIP, MAP3K5,
ER01LB, DNAJB11, ISG15, APOF, SULT1A1, CH25H, INTS7,
LCAT, MAP3K8, CREB3L2, CFH, RPL12, ADAM9, PLD1, F10,
EMG1, YY1, PI 1, PIM3, LOC100044878, ADAMTS4, HACL1,
RAD23B, RBP1, ELL, ZFP612, PFKFB2, HSPA1A, RFFL, HSPA1B,
ARG1, SERPINA1B, SERPINA1A, SERPINA1C, DUSP16, FBX04,
PABPC1, LOC100043996, IKZF4, ST6GAL1, SCD2, SUB1,
OSBPL9, CFB, MAP2K3, TGFBR1, IL1RN, ATP11A, UBE2L6,
TREX1, CHI3L3, CHI3L4, SMAD1, GUCY2C, HNRNPA1, PTPN12,
CYP7B1, CYP17A1, ATP2A2, HOPX, PPRCl, IDIl, BACHl, FOXA3,
GAR1, GNPNAT1, NFKB1, PMVK, HSPH1, RRP1B, SAA1,
SERPINA6, SIK1, SERTAD1, NFKBIZ, ATP4A, LPGAT1, ACNAT2,
MMP19, TLE3, TLE1, SLC3A1, EIF1A, RAD52, GTF2B, BD1,
C8A, SDS, ADK, GADD45G, RBM39, FKBP11, SERP1, HSD3B2,
HSD3B3, HSD3B6, HSD17B2, C3, PRTN3, CREM, HSD3B5, HK2,
EDEM1, PCOLCE, RPL30, STT3A, XBP1, LOC100046232, DHCR7,
GOTERM_ GO:0044238~primary ALOX5AP, BCL3, PREPL, ETV6, ACSL4, QSOX1, PCSK5, RBM25,
249 8,63E-04 1,492617815 BP_ALL metabolic process TMPRSS2, CES6, CAPN8, SPSB4, ACLY, STAT3, PAPOLA, GFPT1,
PTP4A1, NR5A2, CWC22, APOBEC1, H GCR, F13A1, SNRPD3,
MMP8, TIRAP, CNOT7, AGXT, FDFTl, ST3GAL1, LOC100048018,
GATA6, ELOVL3, CLP1, 2010111I01RIK, EGFR, SOCS3, RELA,
RELB, PRKAB1, HAL, CMAH, HES6, SOCS5, GRHL1, TAT, JUNB,
MOXD1, AHR, RCL1, C4BP, CHID1, RIPK2, DNTTIP2, FGFR1,
LITAF, MVD, GLUD1, KMO, ABCA1, SOX9, RIOK2, MED12L,
ISYNA1, FOXQ1, RPL3, GNMT, RUNX1, B4GALT1, GINS1, MAFF,
CSTF3, PTPN2, LOC100045567, BRCA1, IKBKE, ATF4, PPID,
SPCS3, HIVEP2, DNAJB1, PTPN1, SPCS2, DNAJB4, CPB2, DCXR,
ACOX2, METAP1, DPH5, HP, LSS, PAWR, PSPH, AFMID,
SC4MOL, ACVR1B, TD02, ALAS2, CASP4, ITIH1, ANG, HDC,
PR02, ITIH4, ITIH2, ITIH3, NFIL3, M L1, ZCCHC6, EGR1,
HSP90AA1, ARID5A, TARS, CTH, BTG2, CTSC, AKR1D1,
CAMK1D, CYP51, FKBP5, PNP2, TIPARP, UTP6, TRA2A, ASNS,
NFYB, REL, TG 1, NEDD4L, B4GALNT1, CEBPB, CEBPD,
B3GALT1, IRF9, WSB1, SLC35C1, IRF5, SDR42E1, DR1, CBS
APOBEC1, ALDH1L1, HMGCR, F13A1, CNOT7, AGXT, FDFTl,
ST3GAL1, GATA6, CH25H, LCAT, ELOVL3, CREB3L2, RPL12,
2010111I01RIK, PLD1, YY1, RELA, RELB, PRKAB1, HAL, HES6,
GRHL1, LOC100044878, TAT, JUNB, AHR, DNTTIP2, LITAF,
MVD, ELL, ZFP612, KMO, ABCA1, SOX9, MED12L, SLC11A2,
ARG1, ISYNA1, FOXQ1, SERPINA1B, SERPINA1A, SERPINA1C,
RPL3, RUNX1, GINS1, LOC100043996, B4GALT1, IKZF4, MAFF,
ST6GAL1, SCD2, SUB1, LOC100045567, ATP11A, SMAD1,
GUCY2C, BRCA1, CYP7B1, ATF4, CYP17A1, ATP2A2, HOPX,
GOTERM_ GO:0009058~biosynthetic
134 0,001763129 PPRCl, HIVEP2, IDIl, BACHl, DPH5, FOXA3, GNPNAT1, NFKB1, 3,027122402 BP_ALL process
LSS, PAWR, PSPH, PMVK, SC4MOL, ALAS2, ANG, HDC, NOS3,
MKL1, NFIL3, SERTAD1, EGR1, NFKBIZ, HSP90AA1, LPGAT1,
ATP4A, ARID5A, TLE3, TLE1, EIF1A, GTF2B, MBD1, TARS, CTH,
BTG2, SDS, ADK, RBM39, AKR1D1, SERP1, HSD3B2, CYP51,
HSD3B3, HSD3B6, HSD17B2, CREM, HSD3B5, ASNS, NFYB,
RPL30, STT3A, REL, LOC100046232, XBP1, ALOX5AP, DHCR7,
BCL3, ETV6, PCSK5, B4GALNT1, CEBPB, B3GALT1, CEBPD, CES6,
ACLY, STAT3, IRF9, PAPOLA, IRF5, SDR42E1, DR1, GFPT1,
NR5A2, CBS
S100A6, LOC100044206, MARCKSL1, TLR2, NFKB1, VTN,
PAWR, CNOT7, CXCL10, FOS, CASP4, YD88, GATA6, ANG,
IL1B, FAS, YAPl, MKL1, SERTAD1, ADAM9, EGR1, EGFR, BCL10,
HSP90AA1, SOCS3, RELA, LIFR, SOCS5, JUNB, BCL2L11, AHR,
GOTERM_ GO:0048522~positive INHBB, ADRB2, LOC640441, RIPK2, SERP1, FGFR1, CCL2, LITAF,
66 0,001964201 3,366803345 BP_ALL regulation of cellular process C3, CSF1, GLU01, BEX1, NFYB, SOX9, SMOC2, LOC100045000,
REL, BCL3, TRP53INP1, FBX04, THBS1, RUNX1, SYNPO,
B4GALT1, CEBPB, LOC100045567, CEBPD, TGFBR1, SMAD1,
BRCA1, STAT3, CYP7B1, ATF4, PTP4A1, HOPX, HBEGF, NR5A2,
RBM15 TLR2, NFKB1, NFYB, PAWR, SOX9, CNOT7, FOS, MYD88, REL,
GO:0031328~positive
GOTERM_ GATA6, IL1B, BCL3, YAP1, RUNX1, MKL1, SERTAD1, EGR1,
regulation of cellular 30 0,015598204 23,95498983 BP_ALL BCL10, CEBPB, HSP90AA1, CEBPD, RELA, SMADl, AHR, STAT3,
biosynthetic process
ADRB2, ATF4, NR5A2, RBM15, SERP1
TLR2, NFKB1, NFYB, PAWR, SOX9, CNOT7, FOS, MYD88, REL,
GO:0009891~positive
GOTERM_ GATA6, IL1B, BCL3, YAP1, RUNX1, MKL1, SERTAD1, EGR1,
regulation of biosynthetic 30 0,017717849 26,75733812 BP_ALL BCL10, CEBPB, HSP90AA1, CEBPD, RELA, SMADl, AHR, STAT3,
process
ADRB2, ATF4, NR5A2, RBM15, SERP1
KLK1B4, TLR2, NFKB1, NFYB, PAWR, CNOT7, SOX9, FOS,
GO:0009893~positive MYD88, REL, GATA6, IL1B, BCL3, FBX04, YAP1, LBP, RUNX1,
GOTERM_
regulation of metabolic 35 0,019491781 MKL1, SERTAD1, ADAM9, EGR1, BCL10, HSP90AA1, CEBPB, 29,02751012 BP ALL
process CEBPD, LOC100045567, RELA, SMADl, AHR, STAT3, ADRB2,
ATF4, NR5A2, RBM15, SERP1
TLR2, NFKB1, NFYB, PAWR, CNOT7, SOX9, FOS, MYD88, REL,
GO:0031325~positive GATA6, IL1B, BCL3, FBX04, YAP1, RUNX1, MKL1, SERTAD1,
GOTERM_
regulation of cellular 33 0,023584531 ADAM9, EGR1, BCL10, HSP90AA1, CEBPB, CEBPD, 34,01471423 BP_ALL
metabolic process LOC100045567, RELA, SMADl, AHR, STAT3, ADRB2, ATF4,
NR5A2, RBM15, SERP1
TLR2, NFKB1, NFYB, SOX9, CNOT7, FOS, MYD88, REL, GATA6,
GO:0051173~positive
GOTERM_ BCL3, YAP1, RUNX1, MKL1, SERTAD1, EGR1, BCL10, CEBPB,
regulation of nitrogen 28 0,025059338 35,72942742 BP_ALL HSP90AA1, LOC100045567, CEBPD, RELA, SMADl, AHR, STAT3,
compound metabolic process
ADRB2, ATF4, NR5A2, RBM15
NFYB, NFKB1, PAWR, SOX9, CNOT7, FOS, MYD88, REL, GATA6,
GO:0010557~positive
GOTERM_ IL1B, BCL3, YAP1, RUNX1, MKL1, SERTAD1, EGR1, BCL10,
regulation of macromolecule 28 0,027130179 38,06635369 BP_ALL CEBPB, CEBPD, RELA, SMADl, STAT3, AHR, ADRB2, ATF4,
biosynthetic process
NR5A2, RBM15, SERP1
GO:0045893~positive EGR1, BCL10, CEBPB, CEBPD, RELA, NFYB, NFKB1, SMADl,
GOTERM_
regulation of transcription, 23 0,030731586 SOX9, CNOT7, AHR, STAT3, FOS, ADRB2, ATF4, MYD88, REL, 41,94086762 BP_ALL
DNA-dependent GATA6, BCL3, YAP1, RUNX1, NR5A2, RBM15
GO:0051254~positive EGR1, BCL10, CEBPB, CEBPD, RELA, NFYB, NFKB1, SMADl,
GOTERM_
regulation of RNA metabolic 23 0,032547326 SOX9, CNOT7, AH , STAT3, FOS, ADRB2, ATF4, MYD88, REL, 43,8065365 BP_ALL
process GATA6, BCL3, YAP1, RUNX1, NR5A2, RBM15
APOBEC1, HMGCR, F13A1, CNOT7, AGXT, FDFT1, ST3GAL1,
GATA6, LCAT, ELOVL3, CH25H, CREB3L2, RPL12,
2010111I01RIK, PLDl, YYl, RELA, RELB, PRKABl, HES6, GRHL1,
LOC100044878, JUNB, AHR, DNTTIP2, MVD, LITAF, ELL,
ZFP612, KMO, ABCAl, SOX9, MED12L, SLC11A2, ARGl, ISYNAl,
FOXQ1, SERPINA1B, SERPINA1A, SERPINA1C, RPL3, RUNX1,
LOC100043996, GINS1, B4GALT1, IKZF4, MAFF, ST6GAL1,
SCD2, SUB1, LOC100045567, ATP11A, SMADl, GUCY2C,
GOTERM_ GO:0044249~cellular
120 0,035328728 BRCA1, CYP7B1, ATF4, CYP17A1, ATP2A2, HOPX, PPRC1, 46,55519515 BP_ALL biosynthetic process
HIVEP2, IDI1, BACH1, DPH5, FOXA3, GNPNAT1, NFKB1, PAWR,
PSPH, SC4MOL, ALAS2, ANG, HDC, NOS3, MKL1, NFIL3,
SERTAD1, EGR1, NFKBIZ, HSP90AA1, LPGAT1, ATP4A, ARID5A,
TLE3, TLE1, EIF1A, MBD1, GTF2B, TARS, CTH, BTG2, SDS, ADK,
RBM39, AKR1D1, SERP1, CREM, ASNS, NFYB, RPL30, STT3A,
REL, LOC100046232, XBP1, ALOX5AP, BCL3, ETV6, PCSK5,
B4GALNT1, CEBPB, B3GALT1, CEBPD, CES6, ACLY, STAT3, IRF9,
PAPOLA, IRF5, DR1, NR5A2, CBS
NFYB, NFKB1, SOX9, CNOT7, FOS, MYD88, REL, GATA6, BCL3,
GOTERM_ GO:0045941~positive
25 0,038517564 YAP1, RUNX1, MKL1, SERTAD1, EGR1, BCL10, CEBPB, CEBPD, 49,55044964 BP ALL regulation of transcription
RELA, SMADl, STAT3, AHR, ATF4, ADRB2, NR5A2, RBM15
NFKB1, NFYB, PAWR, CNOT7, SOX9, FOS, MYD88, REL, GATA6,
GO:0010604~positive
GOTERM_ IL1B, BCL3, FBX04, YAP1, RUNX1, MKL1, SERTAD1, ADAM9,
regulation of macromolecule 31 0,047825174 57,41384769 BP_ALL EGR1, BCL10, CEBPB, CEBPD, LOC100045567, RELA, SMADl,
metabolic process
AHR, STAT3, ADRB2, ATF4, NR5A2, RBM15, SERP1
GO:0045935~positive
NFYB, NFKB1, SOX9, CNOT7, FOS, MYD88, REL, GATA6, BCL3, regulation of nucleobase,
GOTER _ YAP1, RUNX1, MKL1, SERTAD1, EGR1, BCL10, CEBPB,
nucleoside, nucleotide and 26 0,048084084 57,61510556 BP_ALL LOC100045567, CEBPD, RELA, SMADl, STAT3, AHR, ADRB2,
nucleic acid metabolic
ATF4, NR5A2, RBM15
process
NFYB, NFKB1, SOX9, CNOT7, FOS, MYD88, REL, GATA6, BCL3,
GOTERM_ GO:0010628~positive
25 0,050316586 YAP1, RUNX1, MKL1, SERTAD1, EGR1, BCL10, CEBPB, CEBPD, 59,3136759 BP_ALL regulation of gene expression
RELA, SMADl, STAT3, AHR, ATF4, ADRB2, NR5A2, RBM15 APOBEC1, ALDH1L1, H MGCR, F13A1, SNRPD3, SYNCRIP,
CNOT7, AGXT, DNAJB11, GATA6, CLP1, INTS7, CREB3L2, EMG1,
YY1, RELA, RELB, CMAH, HAL, HES6, GRHLl, TAT, J UNB, AHR,
MOXD1, RCL1, CHID1, DNTTIP2, RAD23B, LITAF, ELL, ZFP612,
GLUD1, KMO, HSPA1A, HSPA1B, SOX9, MED12L, SLC11A2,
ARG1, FOXQ1, FBX04, PABPC1, GNMT, RUNX1,
LOC100043996, GINS1, IKZF4, MAFF, CSTF3, SUB1,
LOC100045567, TREXl, ATPllA, CHI3L3, CHI3L4, SMADl,
GOTERM_ GO:0006807~nitrogen
125 0,069165962 GUCY2C, H NRNPAl, BRCA1, ATF4, ATP2A2, HOPX, PPRC1, 71,30612709 BP_ALL compound metabolic process
H IVEP2, DCXR, BACH1, GAR1, FOXA3, GNPNAT1, NFKB1,
PAWR, PSPH, AFMI D, TD02, A LAS 2, RRP1B, ANG, ITIH1, H DC,
ITIH4, NOS3, ITIH2, ITIH3, MKL1, NFI L3, ZCCHC6, SERTAD1,
EGR1, NFKBIZ, HSP90AA1, ATP4A, ARID5A, TLE3, TLEl, RAD52,
MBDl, GTF2B, TARS, CTH, BTG2, SDS, ADK, RBM39, PNP2,
CREM, UTP6, TRA2A, TIPARP, ASNS, NFYB, REL,
LOC100046232, XBP1, BCL3, ETV6, RBM25, CEBPB, CEBPD,
STAT3, IRF9, PAPOLA, IRF5, DR1, GFPT1, NR5A2, CWC22, CBS
GO:0045944~positive
EGR1, CEBPB, CEBPD, NFKB1, SMADl, SOX9, CNOT7, STAT3,
GOTERM_ regulation of transcription
19 0,069384066 AHR, FOS, ADRB2, ATF4, MYD88, GATA6, BCL3, YAP1, RUNX1, 71,42301395 BP_ALL from RNA polymerase II
NR5A2, RBM15
promoter
APOBEC1, ALDH1L1, H MGCR, SNRPD3, F13A1, SYNCRIP,
CNOT7, AGXT, DNAJB11, GATA6, CLP1, INTS7, CREB3L2, EMG1,
YY1, RELA, RELB, CMAH, HAL, HES6, GRHLl, TAT, JUNB, AHR,
MOXD1, RCL1, DIMTTIP2, RAD23B, LITAF, ZFP612, ELL, GLUD1,
HSPA1A, KMO, HSPA1B, SOX9, MED12L, SLC11A2, ARG 1,
FOXQ1, FBX04, PABPC1, GNMT, RUNX1, LOC100043996,
GINS1, IKZF4, MAFF, CSTF3, SUB1, LOC100045567, TREXl,
GOTERM_ GO:0034641~cellular nitrogen ATPllA, SMADl, GUCY2C, H NRNPAl, BRCA1, ATF4, ATP2A2,
117 0,163413471 95,53084807 BP_ALL compound metabolic process HOPX, PPRC1, HIVEP2, DCXR, BACH1, GAR1, FOXA3, GNPNAT1,
NFKB1, PAWR, PSPH, AFMID, TD02, ALAS2, RRP1B, ANG, HDC,
N0S3, MKL1, NFIL3, ZCCHC6, SERTAD1, EG R1, NFKBIZ,
HSP90AA1, ATP4A, ARID5A, TLE3, TLEl, RAD52, MBDl, GTF2B,
TARS, CTH, BTG2, SDS, ADK, RBM39, PNP2, CREM, UTP6,
TRA2A, ASNS, NFYB, REL, LOC100046232, XBP1, BCL3, ETV6,
RBM25, CEBPB, CEBPD, STAT3, IRF9, PAPOLA, IRF5, DR1,
GFPT1, NR5A2, CWC22, CBS
LDHA, EFNA1, SYNCRIP, ER01LB, MAP3K5, DNAJB11, ISG15,
CH25H, INTS7, LCAT, MAP3K8, CREB3L2, RPL12, PLD1, EMG1,
YY1, PIM1, PIM3, LOC100044878, HACL1, RAD23B, RBP1,
ZFP612, ELL, PFKFB2, HSPA1A, RFFL, HSPA1B, SLC11A2, ARG 1,
SERPINA1B, SERPINA1A, DUSP16, SERPI NA1C, FBX04, PABPC1,
LOC100043996, I KZF4, ST6GAL1, SCD2, SUB1, MAP2K3,
TGFBRl, TREXl, UBE2L6, ATPllA, SMADl, GUCY2C, HNRNPAl,
PTPN12, PPA1, CYP7B1, CYP17A1, ATP2A2, HOPX, PPRC1, IDI1,
BACH 1, FOXA3, GAR1, GNPNAT1, NFKB1, HSPH1, RRP1B,
SERPINA6, NOS3, SIK1, SERTAD1, NFKBIZ, ATP4A, LPGAT1,
CAR14, ACNAT2, TLE3, TLEl, EIFIA, RAD52, GTF2B, M BDl, SDS,
ADK, GADD45G, RBM39, FKBP11, SERP1, CREM, H K2, EDEM1,
PCOLCE, RPL30, STT3A, LOC100046232, XBP1, ALOX5AP, BCL3,
ETV6, ACSL4, PCSK5, QSOX1, RBM25, CES6, SPSB4, ACLY,
GOTERM_ GO:0044237~cellular
212 0,197900681 STAT3, PAPOLA, PTP4A1, GFPT1, NR5A2, CWC22, APOBEC1, 97,85335416 BP_ALL metabolic process
ALDH 1L1, H MGCR, F13A1, SNRPD3, TIRAP, CNOT7, AGXT,
FDFT1, ST3GAL1, GATA6, CLP1, ELOVL3, 2010111I01RIK, EGFR,
SOCS3, RELA, RELB, PRKABl, CMAH, HAL, HES6, SOCS5, GRHLl,
TAT, JUNB, AHR, MOXD1, RCL1, RIPK2, DNTTIP2, FGFR1, LITAF,
MVD, GLUD1, KMO, ABCA1, SOX9, RIOK2, MED12L, ISYNA1,
FOXQ1, RPL3, GNMT, RUNX1, B4GALT1, GINS1, MAFF, CSTF3,
LOC10004S567, PTPN2, CYB561, BRCA1, IKBKE, ATF4, PPI D,
SPCS3, HIVEP2, DNAJBl, PTPNl, SPCS2, DNAJB4, DCXR, ACOX2,
DPH5, PAWR, PSPH, AFMID, SC4MOL, ACVR1B, TD02, ALAS2,
ANG, HDC, MKL1, NFIL3, ZCCHC6, EGR1, HSP90AA1, ARI D5A,
TARS, CTH, BTG2, AKR1D1, CAMK1D, FKBP5, PNP2, TIPARP,
UTP6, TRA2A, ASNS, NFYB, REL, ADH4, TGM1, NEDD4L,
B4GALNT1, CEBPB, B3GALT1, CEBPD, IRF9, WSB1, SLC35C1,
IRF5, DR1, CBS
Figure imgf000099_0001
BACH 1, APOBEC1, FOXA3, S100A9, TIRAP, TLR2, NFKB1,
PDLIM1, PAWR, CNOT7, FOS, MYD88, LOC100048018, ANG,
GATA6, CLP1, CREB3 L2, CFH, IL1B, RAPGEF4, YAP1, MKL1,
NFIL3, SERTADl, ADA 9, EGRl, EGFR, NFKBIZ, BCLIO, GTPBP4,
SOCS3, RELA, YYl, ARID5A, RELB, TLE3, TLE1, HES6, G RHL1,
GO:0060255~regulation of MBD1, GTF2B, JUNB, AH R, INHBB, ADRB2, BTG2, RAB18,
GOTERM_
macromolecule metabolic 91 0,631446987 RIPK2, DNTTIP2, RBM39, SERP1, FGFR1, LITAF, ELL, ZFP612, 99,99999719 BP_ALL
process CREM, NFYB, SOX9, M ED12L, FOXQ1, REL, LOC100046232,
XBP1, BCL3, FBX04, SKIL, RUNXl, ETV6, LOC100043996, IKZF4,
MAFF, CEBPB, SUB1, LOC100045567, CEBPD, MAP2K3,
TGFBR1, UBE2L6, SMAD1, BRCA1, STAT3, IRF9, ATF4, IRF5,
DR1, ETS2, H2AFY2, HOPX, PPRC1, HIVEP2, TMPO, NR5A2,
RBM15, CBS
BACH 1, APOBEC1, FOXA3, NFKB1, CNOT7, FOS, MYD88,
GATA6, CREB3L2, YAP1, NFIL3, EGRl, BCLIO, RELA, YYl, RELB,
TLE3, TLE1, HES6, GTF2B, JU NB, AHR, ADRB2, RAB18, ZFP612,
GOTERM_ GO:0051252~regulation of
50 0,650335123 CREM, NFYB, SOX9, MED12L, FOXQ1, REL, XBP1, 99,99999888 BP_ALL RNA metabolic process
LOC100046232, BCL3, SKIL, RUNXl, ETV6, MAFF, IKZF4, CEBPB,
CEBPD, SUB1, SMAD1, STAT3, IRF9, ATF4, IRF5, ETS2, HOPX,
NR5A2, RBM15
APOBEC1, H MGCR, SNRPD3, F13A1, SYNCRIP, CNOT7,
DNAJB11, GATA6, INTS7, CLP1, CREB3L2, EMG 1, YYl, RELA,
RELB, CMAH, HES6, GRHL1, JUNB, AHR, RCL1, DNTTIP2,
RAD23 B, LITAF, ZFP612, ELL, HSPA1A, KMO, HSPA1B, SOX9,
MED12L, FOXQ1, FBX04, PABPC1, GNMT, RUNXl,
GO:0006139~nucleobase, LOC100043996, GINS1, MAFF, IKZF4, CSTF3, LOC100045567,
GOTERM_ nucleoside, nucleotide and SUB1, ATP11A, TREX1, SMAD1, GUCY2C, HNRNPA1, BRCA1,
97 0,655755755 99,99999914 BP_ALL nucleic acid metabolic ATF4, ATP2A2, PPRC1, HOPX, HIVEP2, DCXR, BACH1, GAR1,
process FOXA3, G NPNAT1, NFKB1, PAWR, RRP1B, ANG, NFIL3, MKL1,
ZCCHC6, SERTADl, EGRl, NFKBIZ, ATP4A, ARID5A, TLE3, TLE1,
RAD52, MBD1, GTF2B, TARS, BTG2, ADK, RBM39, PNP2, CREM,
UTP6, TRA2A, NFYB, REL, XBP1, LOC100046232, BCL3, ETV6,
RBM25, CEBPB, CEBPD, STAT3, IRF9, PAPOLA, IRF5, DR1,
CWC22, NR5A2
BACH1, FOXA3, NFKB1, CNOT7, FOS, MYD88, GATA6, CREB3L2,
YAP1, NFIL3, EGRl, BCLIO, RELA, YYl, RELB, TLE3, TLE1, HES6,
GOTERM_ GO:0006355~regulation of GTF2B, JUNB, AH R, ADRB2, RAB18, ZFP612, CREM, NFYB,
49 0,663125317 99,99999941 BP_ALL transcription, DNA-dependent SOX9, MED12L, FOXQ1, REL, XBP1, LOC100046232, BCL3, SKIL,
RU NXl, ETV6, MAFF, IKZF4, CEBPB, CEBPD, SUB1, SMAD1,
STAT3, IRF9, ATF4, IRF5, ETS2, HOPX, NR5A2, RBM15
BACH1, APOBEC1, FOXA3, F13A1, NFKB1, PAWR, CNOT7,
ST3GAL1, ALAS2, ANG, GATA6, LCAT, CREB3L2, RPL12, MKL1,
NFIL3, SERTADl, EGRl, NFKBIZ, RELA, YYl, RELB, ARID5A, TLE3,
TLE1, HES6, EIF1A, GRHL1, MBD1, GTF2B, JUNB, AH R, TARS,
GO:0034645~cellular BTG2, DNTTIP2, RBM39, SERP1, LITAF, ELL, ZFP612, CREM,
GOTERM_
macromolecule biosYnthetic 79 0,726625239 NFYB, ABCA1, SOX9, MED12L, FOXQ1, RPL30, STT3A, 99,99999998 BP_ALL
process SERPINA1B, REL, LOC100046232, XBP1, SERPINA1A,
SERPINA1C, RPL3, BCL3, RUNXl, ETV6, LOC100043996,
B4GALT1, GINS1, IKZF4, MAFF, ST6GAL1, CEBPB, SUB1, CEBPD,
B3GALT1, CES6, SMAD1, BRCA1, STAT3, IRF9, ATF4, PAPOLA,
IRF5, DR1, HOPX, PPRC1, HIVEP2, N R5A2
BACH1, APOBEC1, FOXA3, F13A1, NFKB1, PAWR, CNOT7,
ST3GAL1, ALAS2, ANG, GATA6, LCAT, CREB3L2, RPL12, MKL1,
NFIL3, SERTADl, EGRl, NFKBIZ, RELA, YYl, RELB, ARI D5A, TLE3,
TLE1, HES6, EIF1A, GRH L1, MBD1, GTF2B, JUNB, AH R, TARS,
BTG2, DNTTIP2, RBM39, SERP1, LITAF, ELL, ZFP612, CREM,
GOTER _ GO. 009059~macromolecule
79 0,737661963 NFYB, ABCA1, SOX9, MED12L, FOXQ1, RPL30, STT3A, 99,99999999 BP ALL biosynthetic process
SERPINA1B, REL, LOC100046232, XBP1, SERPINA1A,
SERPINA1C, RPL3, BCL3, RUNXl, ETV6, LOC100043996,
B4GALT1, GINS1, IKZF4, MAFF, ST6GAL1, CEBPB, SUB1, CEBPD,
B3GALT1, CES6, SMAD1, BRCA1, STAT3, IRF9, ATF4, PAPOLA,
IRF5, DR1, HOPX, PPRC1, H IVEP2, NR5A2
BACH1, APOBEC1, KLK1B4, FOXA3, TIRAP, TLR2, NFKB1,
PDLIMl, PAWR, CNOT7, FOS, MYD88, LOC100048018, ANG,
GATA6, CREB3L2, CFH, IL1B, RAPGEF4, YAP1, MKL1, NFIL3,
SERTADl, ADAM9, EGRl, EGFR, NFKBIZ, BCLIO, GTPBP4,
SOCS3, RELA, YYl, ARID5A, RELB, TLE3, TLE1, HES6, GRHL1,
GOTERM_ GO:0080090~regulation of M BD1, GTF2B, JUNB, AHR, ADRB2, BTG2, RAB18, RIPK2,
87 0,772767951 100 BP_ALL primary metabolic process DNTTIP2, RBM39, SERP1, LITAF, ELL, ZFP612, CREM, NFYB,
SOX9, MED12L, FOXQ1, REL, LOC100046232, XBP1, BCL3,
FBX04, SKIL, GNMT, RUNXl, ETV6, ACSL4, LOC100043996,
IKZF4, MAFF, CEBPB, SUB1, LOC100045567, CEBPD, UBE2L6,
SMAD1, BRCA1, STAT3, IRF9, ATF4, IRF5, DR1, ETS2, HOPX,
PPRC1, HIVEP2, TMPO, NR5A2, RBM15, CBS BACH l, FOXA3, NFKBl, PAWR, CNOT7, GATA6, ANG, CREB3L2,
MKL1, NFIL3, SERTAD1, EGR1, NFKBIZ, RELA, YY1, RELB, ARID5A, TLE3, TLE1, HES6, GRHL1, GTF2B, MBD1, JUNB, AHR,
GOTERM_ BTG2, DNTTIP2, RBM39, LITAF, ZFP612, ELL, CREM, IM FYB,
GO:O006350~transcription 57 0,773694426 100 BP ALL SOX9, MED12L, FOXQl, REL, XBPl, LOC100046232, BCL3,
RUNXl, ETV6, LOC100043996, MAFF, I KZF4, CEBPB, CEBPD, SUB1, SMAD1, STAT3, IRF9, ATF4, PAPOLA, IRF5, DR1, PPRC1, HOPX, HIVEP2, NR5A2
APOBEC1, EFNA1, F13A1, SNRPD3, TIRAP, SYNCRIP, CNOT7, ST3GAL1, ER01LB, MAP3K5, DNAJB11, ISG15, GATA6, CLP1, LCAT, INTS7, MAP3K8, CREB3L2, RPL12, EGFR, SOCS3, EMG1, RELA, YY1, RELB, PIM1, PIM3, HES6, SOCS5, GRH L1,
LOC100044878, JUNB, AHR, RCL1, RIPK2, DNTTIP2, FGFR1, RAD23B, LITAF, ELL, ZFP612, HSPA1A, RFFL, HSPA1B, ABCA1, SOX9, RIOK2, MED12L, FOXQl, SERPINA1B, SERPINA1A, DUSP16, SERPINA1C, RPL3, FBX04, PABPC1, GNMT, RUNXl, GINS1, LOC100043996, B4GALT1, IKZF4, MAFF, CSTF3,
GO:0044260~cellular ST6GAL1, SUB1, PTPN2, MAP2K3, TGFBR1, TREX1, UBE2L6,
GOTERM_
macromolecule metabolic 150 0,782738283 SMAD1, GUCY2C, HNRNPA1, BRCA1, PTPN12, IKBKE, ATF4, 100 BP ALL
process PPID, SPCS3, HOPX, PPRC1, HIVEP2, PTPN1, SPCS2, DNAJB1,
DNAJB4, BACHl, FOXA3, DPH5, GARl, NFKBl, PAWR, ACVRIB, HSPH 1, ALAS2, RRP1B, ANG, MKL1, NFIL3, SIK1, ZCCHC6, SERTAD1, EGR1, NFKBIZ, HSP90AA1, ARID5A, TLE3, TLE1, EIF1A, RAD52, GTF2B, MBD1, TARS, BTG2, GADD45G, RBM39, FKBPll, SERPl, CAMKID, FKBP5, CREM, TIPARP, UTP6, TRA2A, NFYB, EDEM1, PCOLCE, RPL30, STT3A, REL, LOC100046232, XBP1, TGM1, BCL3, NEDD4L, ETV6, QSOX1, RBM25, CEBPB, B3GALT1, CEBPD, CES6, SPSB4, STAT3, I RF9, WSB1, PAPOLA, IRF5, PTP4A1, DR1, NR5A2, CWC22
BACHl, APOBEC1, FOXA3, TLR2, NFKBl, PDLIM1, PAWR, CNOT7, FOS, MYD88, LOC100048018, ANG, GATA6, CLP1, CREB3L2, CFH, YAP1, MKL1, NFIL3, SERTAD1, EGR1, BCL10, NFKBIZ, GTPBP4, RELA, YY1, RELB, ARID5A, TLE3, TLE1, HES6, GRH L1, MBD1, GTF2B, JUNB, AH R, ADRB2, BTG2, RAB18,
GOTER _ GO:0010468~regulation of
78 0,804276774 RIPK2, DNTTIP2, RBM39, SERPl, FGFR1, LITAF, ZFP612, ELL, 100 BP_ALL gene expression
CREM, NFYB, SOX9, MED12L, FOXQl, REL, LOC100046232, XBPl, BCL3, SKIL, RUNXl, ETV6, LOC100043996, IKZF4, MAFF, CEBPB, CEBPD, SUB1, TGFBR1, SMAD1, BRCA1, STAT3, IRF9, ATF4, IRF5, DR1, ETS2, H2AFY2, HOPX, PPRC1, H IVEP2, TMPO, NR5A2, RBM15
BACHl, FOXA3, S100A9, TLR2, NFKBl, PDLIM 1, PAWR, CNOT7, FOS, MYD88, DYNLL1, ANG, GATA6, CREB3L2, IL1B, YAP1, MKL1, NFIL3, SERTAD1, EGR1, BCL10, NFKBIZ, GTPBP4,
HSP90AA1, RELA, YY1, RELB, ARID5A, TLE3, TLE1, HES6, G RHL1, MBD1, GTF2B, JUNB, AHR, INH BB, ADRB2, RAB18, BTG ,
GOTER _ GO:0009889~regulation of
79 0,823015858 RIPK2, DNTTIP2, RBM39, SERPl, LITAF, ZFP612, ELL, CREM, 100 BP_ALL biosynthetic process
NFYB, SOX9, MED12L, FOXQl, REL, LOC100046232, XBPl, BCL3, SKIL, GNMT, RUNXl, ETV6, LOC100043996, IKZF4, MAFF, CEBPB, SUB1, CEBPD, MAP2K3, SMAD1, BRCA1, STAT3, IRF9, ATF4, IRF5, DR1, ETS2, HOPX, PPRC1, HIVEP2, TMPO, NR5A2, RBM15
BACH l, FOXA3, TLR2, NFKBl, PDLIM1, PAWR, CNOT7, FOS, MYD88, DYNLL1, ANG, GATA6, CREB3L2, IL1B, YAP1, M KL1, NFIL3, SERTAD1, EGR1, BCL10, NFKBIZ, GTPBP4, HSP90AA1, RELA, YYl, RELB, ARID5A, TLE3, TLE1, HES6, GRHL1, MBD1,
GOTERM_ GO:0031326~regulation of GTF2B, JUNB, AH R, INHBB, ADRB2, RAB18, BTG2, RIPK2,
78 0,844784047 100 BP_ALL cellular biosynthetic process DNTTIP2, RBM39, SERPl, LITAF, ZFP612, ELL, CREM, NFYB,
SOX9, MED12L, FOXQl, REL, LOC100046232, XBPl, BCL3, SKIL, GNMT, RUNXl, ETV6, LOC100043996, IKZF4, MAFF, CEBPB, CEBPD, SUB1, MAP2K3, SMAD1, BRCA1, STAT3, IRF9, ATF4, IRF5, DR1, ETS2, HOPX, PPRC1, HIVEP2, TMPO, NR5A2, RBM15
BACHl, FOXA3, S100A9, TLR2, NFKBl, PDLIMl, PAWR, CNOT7, FOS, MYD88, ANG, GATA6, CREB3L2, IL1B, YAP1, MKL1, NFIL3, SERTAD1, EGR1, BCL10, NFKBIZ, GTPBP4, RELA, YYl, RELB, ARID5A, TLE3, TLE1, H ES6, GRH L1, MBD1, GTF2B, JUNB, AH R,
GO:0010556~regulation of
GOTER _ INHBB, ADRB2, RAB18, BTG2, RIPK2, DNTTIP2, RBM39, SERPl, macromolecule biosynthetic 75 0,849549504 100 BP_ALL LITAF, ZFP612, ELL, CREM, NFYB, SOX9, MED12L, FOXQl, REL, process
LOC100046232, XBPl, BCL3, SKIL, RUNXl, ETV6,
LOC100043996, IKZF4, MAFF, CEBPB, CEBPD, SUB1, MAP2K3, SMAD1, STAT3, IRF9, ATF4, IRF5, DR1, ETS2, HOPX, PPRC1, H IVEP2, TMPO, NR5A2, RBM15 S100A6, LOC100044206, EFNA1, KLK1B4, S100A9, FST,
PDLI 1, MAP3K5, MYD88, MAP3K8, CFH, CREB3L2, RAPGEF4, FAS, RAB20, ADAM9, GTPBP4, F10, YY1, PIM1, LIFR, FARP1, BCL2L11, RND3, KRT18, RAB18, CCR2, UNC13B, IL1R1, RBP1, ELL, ZFP612, AKAP12, HSPA1A, HSPA1B, SLC11A2, PPAN, LOC100045000, DUSP16, FBX04, FGL1, LOC100043996, GNAT1, IKZF4, G PR155, SCD2, SUB1, CFB, MAP2K3, TGFBR1, IL1RN, UBE2L6, CELSR1, SMAD1, GUCY2C, GNAT2, CYP7B1, CYP17A1, RGS1, LAMA3, ATP2A2, ETS2, HOPX, AVPR1A, PPRC1, CML2, BACH1, MARCKSL1, FOXA3, FER T2, PDIA6, NFKB1, PDIA5, PDIA4, DYNLL1, SERPINA6, BAG3, IL1RAP, NOS3, SIK1, SERTADl, NFKBIZ, ICAM1, ATP4A, TLE3, TLE1, GTF2B, MBD1, INHBB, C8A, GRM8, GADD45G, RBM39,
GADD45A, SERP1, C3, CCR1, CREM, CSF1, XBPl,
LOC100046232, DHCR7, TRP53 INP1, BCL3, THBS1, ETV6,
GOTER _ GO:0065007~biological ACSL4, QSOX1, PCSK5, LOC637082, RRBP1, SPSB4, BIRC2,
227 0,863394709 100 BP_ALL regulation STAT3, RAB32, OR 1, RASSF5, PTP4A1, H BEGF, NR5A2,
RBM 15, CD14, ORM2, ORM3, APOBECl, HMGCR, F13A1, TLR2, TIRAP, VTN, CNOT7, CXCL10, TIAM2, LOC100048018, GATA6, CLP1, PDE4B, IL1B, SPRED1, DNAJC3, EGFR, BCL10, SOCS3, RELA, RELB, HES6, SOCSS, TACC3, GRHL1, JUNB, AHR, TACC2, C4BP, TH BD, RIPK2, DNTTIP2, FGFRl, CCL2, LITAF, MCLl, GRB2, IFITM3, GLUD1, BEX1, NEDD9, SOX9, MED12L, TIMP1, FOXQl, FGA, SLC30A1, SKIL, GNMT, RUNX1, FGD6, TRAF3, FN1, B4GALT1, MAFF, LOC100045567, BRCA1, LOC100048453, ATF4, H IVEP2, WIF1, TMPO, CPB2, SCARA5, PRDX4, PAWR, ANK, FOS, ALAS2, CASP4, ANG, PROZ, MT2, MT1, YRDC, YAPl, LBP, NFIL3, MKLl, TNIP2, PPP1R14A, ARHGAP9, EGRl,
HSP90AA1, ARI D5A, TIFA, MID1IP1, SLC9A3R1, ADRB2,
LOC640441, BTG2, NUCB2, BTG3, CAMK1D, NFYB, SMOC2, REL, KRT8, NEDD4L, SLC39A4, SYNPO, CEBPB, CEBPD, RCAN1, IRF9, WSB1, IRF5, GPR110, DR1, H2AFY2, IGFBP1, CBS
BACH 1, APOBECl, FOXA3, TLR2, NFKB1, PDLI M 1, PAWR, CNOT7, FOS, YD88, DYNLL1, GATA6, CREB3L2, YAPl, MKLl, NFIL3, SERTADl, EGRl, BCL10, NFKBIZ, GTPBP4, HSP90AA1, RELA, YY1, RELB, ARID5A, TLE3, TLE1, HES6, GRHL1, MBD1,
GO:0051171~regulation of
GOTERM_ GTF2B, JUNB, AHR, ADRB2, RAB18, BTG2, RIPK2, DNTTIP2,
nitrogen compound 73 0,894587508 100 BP_ALL RBM39, LITAF, ZFP612, ELL, CREM, NFYB, SOX9, MED12L,
metabolic process
FOXQl, REL, LOC100046232, XBPl, BCL3, SKIL, RUNX1, ETV6, LOC100043996, IKZF4, MAFF, CEBPB, LOC100045567, CEBPD, SUB1, SMAD1, STAT3, IRF9, ATF4, IRF5, DR1, ETS2, HOPX, PPRC1, HIVEP2, TMPO, NR5A2, RBM15
BACH 1, FOXA3, TLR2, NFKB1, PDLIM1, PAWR, CNOT7, FOS, MYD88, GATA6, CREB3L2, YAPl, MKLl, NFIL3, SERTADl, EGRl, BCL10, NFKBIZ, RELA, YY1, RELB, ARID5A, TLE3, TLE1, HES6, GRH L1, MBD1, GTF2B, JUNB, AH R, ADRB2, RAB18, BTG2,
GOTERM_ GO:0045449~regulation of
68 0,900914108 RIPK2, DNTTIP2, RBM39, LITAF, ZFP612, ELL, CREM, NFYB, 100 BP_ALL transcription
SOX9, MED12L, FOXQl, REL, XBPl, LOC100046232, BCL3, SKIL, RUNX1, ETV6, LOC100043996, IKZF4, MAFF, CEBPB, CEBPD, SUB1, SMAD1, STAT3, IRF9, ATF4, IRF5, DR1, ETS2, HOPX, PPRC1, HIVEP2, TMPO, NR5A2, RBM15
S100A6, LOC100044206, EFNA1, KLK1B4, S100A9, FST,
PDLIM1, MAP3K5, YD88, MAP3K8, CFH, CREB3L2, RAPGEF4,
FAS, RAB20, ADA 9, GTPBP4, YY1, PIM1, LIFR, FARP1,
BCL2L11, RND3, KRT18, RAB18, CCR2, UNC13B, IL1R1, ELL,
ZFP612, AKAP12, HSPA1A, HSPA1B, LOC100045000, PPAN,
DUSP16, FBX04, FGLl, LOC100043996, GNATl, IKZF4, GPR155,
SUB1, CFB, MAP2K3, TGFBR1, UBE2L6, CELSRl, SMAD1,
GUCY2C, GNAT2, CYP7B1, LAMA3, RGSl, ATP2A2, ETS2, HOPX,
AVPR1A, PPRC1, C L2, BACH 1, MARCKSL1, FOXA3, FERMT2,
PDIA6, NFKB1, PDIA5, PDIA4, DYNLL1, BAG3, IL1RAP, NOS3,
SIK1, SERTAD1, ICAM1, NFKBIZ, ATP4A, TLE3, TLE1, GTF2B,
MBD1, C8A, IIMHBB, GRM8, GADD45G, RBM39, GADD45A,
SERP1, C3, CREM, CCR1, CSF1, LOC100046232, XBP1, DHCR7,
TRP53INP1, BCL3, THBS1, ETV6, ACSL4, QSOX1, LOC637082,
GOTERM_ GO:0050789~regulation of RRBP1, SPSB4, BIRC2, STAT3, RAB32, ORM1, RASSF5, PTP4A1,
212 0,909614438 100 BP ALL biological process HBEGF, NR5A2, RBM15, ORM2, CD14, OR 3, APOBEC1,
HMGCR, TIRAP, TLR2, VTN, CNOT7, CXCL10, TIAM2,
LOC100048018, GATA6, CLP1, PDE4B, I L1B, SPRED1, DNAJC3,
EGFR, BCL10, SOCS3, RELA, RELB, HES6, SOCS5, TACC3, GRH L1,
JUNB, AHR, TACC2, C4BP, TH BD, RIPK2, DNTTIP2, FGFRl, CCL2,
LITAF, MCL1, GRB2, GLUD1, IFITM3, BEX1, NEDD9, SOX9,
TIMP1, MED12L, FOXQl, FGA, SKI L, GNMT, RUNX1, FGD6,
TRAF3, FN1, B4GALT1, MAFF, LOC100045567, BRCA1,
LOC100048453, ATF4, HIVEP2, WIFl, TMPO, CPB2, PRDX4,
PAWR, ANK, FOS, CASP4, ANG, MT2, MT1, YRDC, YAP1, LBP,
NFIL3, MKL1, TNIP2, PPP1R14A, ARHGAP9, EGR1, HSP90AA1,
ARID5A, TIFA, MID1IP1, SLC9A3R1, ADRB2, LOC640441, BTG2,
BTG3, CAMK1D, NFYB, SMOC2, REL, KRT8, N EDD4L, SYNPO,
CEBPB, CEBPD, RCAN1, IRF9, WSB1, IRF5, GPR110, DR1,
H2AFY2, IGFBP1, CBS
BACH1, APOBEC1, FOXA3, TLR2, NFKB1, PDLIM 1, PAWR,
CNOT7, FOS, MYD88, GATA6, CREB3L2, YAP1, MKL1, NFIL3,
SERTAD1, EGR1, BCL10, NFKBIZ, GTPBP4, RELA, YY1, RELB,
GO:0019219~regulation of ARID5A, TLE3, TLE1, HES6, GRHL1, MBD1, GTF2B, J UNB, AHR,
GOTERM_ nucleobase, nucleoside, ADRB2, RAB18, BTG2, RIPK2, DNTTIP2, RBM39, LITAF, ZFP612,
71 0,923424766 100 BP_ALL nucleotide and nucleic acid ELL, CREM, NFYB, SOX9, ED12L, FOXQl, REL, LOC100046232,
metabolic process XBP1, BCL3, SKIL, RUNX1, ETV6, LOC100043996, IKZF4, MAFF,
CEBPB, LOC100045567, CEBPD, SUB1, SMAD1, STAT3, IRF9,
ATF4, IRF5, DR1, ETS2, HOPX, PPRC1, H IVEP2, TMPO, NR5A2,
RBM15
S100A6, LOC100044206, KLK1B4, EFNA1, FST, S100A9,
PDLIMl, MAP3K5, MYD88, MAP3K8, CREB3L2, RAPGEF4, FAS,
RAB20, ADAM9, GTPBP4, YY1, LIFR, PIM1, BCL2L11, FARP1,
RND3, KRT18, RAB18, CCR2, UNC13B, IL1R1, ZFP612, ELL,
AKAP12, HSPA1A, HSPA1B, LOC100045000, PPAN, DUSP16,
FBX04, FGLl, LOC100043996, GNATl, G PR155, IKZF4, SUB1,
TGFBR1, MAP2K3, SMAD1, CELSRl, GUCY2C, GNAT2, CYP7B1,
LAMA3, RGSl, ETS2, AVPR1A, PPRC1, HOPX, CML2, BACH1,
MARCKSL1, FOXA3, FERMT2, PDIA6, NFKB1, PDIA5, PDIA4,
DYNLL1, BAG3, IL1RAP, NOS3, SIK1, SERTAD1, NFKBIZ, ICAM1,
TLE3, TLE1, MBD1, GTF2B, INH BB, GRM8, GADD45G, RBM39,
GADD45A, SERP1, C3, CCR1, CREM, CSF1, XBP1,
LOC100046232, DHCR7, BCL3, TRP53INP1, ACSL4, ETV6,
GOTERM_ GO:0050794~regulation of
192 0,985827169 TH BS1, QSOX1, LOC637082, RRBP1, SPSB4, BIRC2, STAT3, 100 BP_ALL cellular process
RAB32, RASSF5, PTP4A1, HBEGF, NR5A2, RBM15, APOBEC1,
HMGCR, TIRAP, TLR2, VTN, CNOT7, CXCL10, TIAM2, GATA6,
PDE4B, IL1B, SPRED1, DNAJC3, EGFR, BCL10, SOCS3, RELA,
RELB, SOCS5, HES6, GRH L1, TACC3, JUNB, AHR, TACC2, RIPK2,
DNTTIP2, FGFRl, CCL2, MCL1, LITAF, GRB2, GLUD1, IFITM3,
BEX1, SOX9, TIMP1, MED12L, FOXQl, FGA, SKIL, GNMT,
RUNX1, FGD6, FN1, TRAF3, B4GALT1, MAFF, LOC100045567,
BRCA1, ATF4, LOC100048453, HIVEP2, WIFl, TMPO, PRDX4,
PAWR, FOS, CASP4, ANG, MT2, MT1, YAP1, TNIP2, NFIL3,
MKL1, PPP1R14A, ARHGAP9, EGR1, HSP90AA1, ARID5A, TIFA,
MID1IP1, SLC9A3R1, ADRB2, BTG2, LOC640441, BTG3,
CAMK1D, NFYB, SMOC2, REL, KRT8, SYNPO, CEBPB, CEBPD,
RCAN1, WSB1, IRF9, IRF5, GPR110, DR1, IGFBP1, CBS
Annotation Enrichment Score:
Cluster 34 0.9009561535662886
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0044236~multicellular
4 0,058530919 PRTN3, TIPARP, MMP8, MMP19 65,02718379 BP ALL organismal metabolic process GOTERM_ GO:0030S74~collagen
3 0,114337291 PRTN3, MMP8, MMP19 87,9365032 BP ALL catabolic process
GOTERM_ GO:0044243~multicellular
3 0,125822558 PRTN3, MMP8, MMP19 90,38986191 BP ALL organismal catabolic process
GOTER _ GO:0032963~collagen
3 0,186528999 PRTN3, MMP8, MP19 97,25679507 BP ALL metabolic process
GO:0044259~multicellular
GOTERM_
organismal macromolecule 3 0,19913203 PRTN3, M P8, MMP19 97,91003935 BP_ALL
metabolic process
Annotation Enrichment Score:
Cluster 35 0.8734916657874373
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0016051~carbohydrate
7 0,065973235 B4GALT1, ATF4, ISYNA1, B3GALT1, SDS, GFPT1, GNPNAT1 69,54264364 BP ALL biosynthetic process
GO:0034637~cellular
GOTERM_
carbohydrate biosynthetic 5 0,126070417 B4GALT1, ATF4, ISYNA1, SDS, GNPNAT1 90,43721467 BP_ALL
process
GOTERM_ GO:0046165~alcohol
4 0,133422663 ATF4, ISYNA1, SDS, GNPNAT1 91,74584703 BP ALL biosynthetic process
GOTERM_ GO:0046364~monosaccharide
3 0,288950042 ATF4, SDS, GNPNAT1 99,73681325 BP ALL biosynthetic process
Annotation Enrichment Score:
Cluster 36 0.8633721621902434
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051258~protein FGA, ANG, TUBB6, TUBAIA, LOC100045728, TUBAIB, TUBAIC,
6 0,011496118 18,24225075 BP ALL polymerization LOC100044416
HIST2H3C2, HIST2H3C1, LOC100045728, LOC100044416, FGA,
GO:0034622~cellular ANG, CLP1, TUBB6, TUBAIA, TUBAIB, TUBAIC, HIST2H3B,
GOTER _
macromolecular complex 14 0,037249193 TSRl, LOC100045490, H2AFY3, HIST1H3A, H2AFY2, HIST1H3B, 48,37854428 BP ALL
assembly HIST1H3C, H3F3A, HIST1H3D, H3F3B, HIST1H3E, HIST1H3F,
UNC13B, HIST1H3G, HIST1H3H, HIST1H3I
HIST2H3C2, HIST2H3C1, LOC100045728, LOC100044416, FGA,
ANG, CLP1, TUBB6, GNMT, FAS, TUBAIA, TUBAIB, TUBAIC,
GOTERM_ GO:0065003~macromolecular HIST2H3B, BCL10, TSRl, LOC100045490, GTF2B, H2AFY3,
19 0,044445168 54,70245698 BP_ALL complex assembly H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
HIST1H3D, HIST1H3E, HIST1H3F, UNC13B, SCARA5, HIST1H3G,
HIST1H3H, HIST1H3I
GAR1, UTP6, HIST2H3C2, HIST2H3C1, LOC100045728,
LOC100044416, FGA, RRP1B, ANG, CLP1, TUBB6, FAS, GNMT,
TUBAIA, GNL2, TUBAIB, TUBAIC, FN1, BCL10, HIST2H3B,
GOTER _ GO:0044085~cellular
29 0,080775001 GTPBP4, TSRl, EMG1, BYSL, LOC100045490, GTF2B, RCL1, 76,94056112 BP_ALL component biogenesis
TNS1, H2AFY3, H2AFY2, HIST1H3A, HIST1H3B, HIST1H3C,
H3F3A, HIST1H3D, H3F3B, HIST1H3E, HIST1H3F, HIST1H3G,
UNC13B, SCARA5, HIST1H3H, HIST1H3I
HIST2H3C2, HIST2H3C1, LOC100045728, LOC100044416, FGA,
GO:0034621~cellular ANG, CLP1, TUBB6, TUBAIA, TUBAIB, TUBAIC, HIST2H3B,
GOTERM_
macromolecular complex 14 0,080796128 TSRl, LOC100045490, H2AFY3, HIST1H3A, H2AFY2, HIST1H3B, 76,94979132 BP_ALL
subunit organization HIST1H3C, H3F3A, HIST1H3D, H3F3B, HIST1H3E, HIST1H3F,
UNC13B, HIST1H3G, HIST1H3H, HIST1H3I
HIST2H3C2, HIST2H3C1, LOC100045728, LOC100044416, FGA,
ANG, CLP1, TUBB6, GNMT, FAS, TUBAIA, TUBAIB, TUBAIC,
GOTER _ GO:0043933~macromolecular HIST2H3B, BCL10, TSR1, LOC100045490, GTF2B, H2AFY3,
19 0,083294 78,01686068 BP_ALL complex subunit organization H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
HIST1H3D, HIST1H3E, HIST1H3F, UNC13B, SCARA5, HIST1H3G,
HIST1H3H, HIST1H3I
BCL10, GTF2B, LOC100045728, LOC100044416, FGA, ANG,
GOTERM_ GO:0070271~protein complex
12 0,159916258 TUBB6, GNMT, FAS, TUBAIA, TUBAIB, SCARA5, UNC13B, 95,19400683 BP_ALL biogenesis
TUBAIC
BCL10, GTF2B, LOC100045728, LOC100044416, FGA, ANG,
GOTERM_ GO:0006461~protein complex
12 0,159916258 TUBB6, GNMT, FAS, TUBAIA, TUBAIB, SCARA5, UNC13B, 95,19400683 BP_ALL assembly
TUBAIC
GOTERM_ GO:0043623~cellular protein FGA, ANG, TUBB6, TUBAIA, LOC100045728, UNC13B, TUBAIB,
7 0,16794766 95,93451195 BP ALL complex assembly TUBAIC, LOC100044416
GOTERM_ GO:0051260~protein
4 0,274487072 BCL10, GNMT, FAS, SCARA5 99,62623989 BP ALL homooligomerization HIST2H3C2, HIST2H3C1, LOC100045728, LOC100044416, FGA,
ANG, CLP1, TUBB6, GNMT, FAS, TUBA1A, TUBA1B, TUBA1C,
GOTERM_ GO:0022607~cellular FN1, HIST2H3B, BCL10, TSR1, LOC100045490, GTF2B, TNS1,
21 0,327370844 99,89999005 BP_ALL component assembly H2AFY3, H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C,
H3F3B, HIST1H3D, HIST1H3E, HIST1H3F, UNC13B, SCARA5,
HIST1H3G, HIST1H3H, HIST1H3I
GOTERM_ GO:0051259~protein
4 0,452484067 BCL10, GNMT, FAS, SCARA5 99,99722565 BP ALL oligomerization
GOTERM_ GO:0007018~microtubule- DYNLL1, TUBB6, TUBA1A, LOC100045728, TUBA1B, TUBA1C,
5 0,459762174 99,99780251 BP ALL based movement LOC100044416
HIP1R, S100A9, VTN, LOC100044416, ANG, CLP1, TUBB6, FAS,
LBP, TUBA1A, TUBA1B, TUBA1C, EGFR, BCL10, LOC100045490,
TACC3, GTF2B, TACC2, FMN2, ADRB2, TNS1, TAGLN, UNC13B,
GADD45A, FGFRl, GGCT, NEDD9, HIST2H3C2, HSPAIA,
GOTERM_ GO:0016043~cellular HIST2H3C1, HSPAIB, ABCA1, SOX9, LOC100045728, ALCAM,
51 0,984823146 100 BP_ALL component organization SLC11A2, SMOC2, FGA, KRT8, BCL3, FBX04, GNMT, FN1,
SYNPO, B4GALT1, HIST2H3B, TSR1, TGFBR1, BRCA1, NOLC1,
H2AFY3, SVIL, H2AFY2, HIST1H3A, HOPX, HIST1H3B, HIST1H3C,
H3F3A, HIST1H3D, H3F3B, HIST1H3E, HIST1H3F, HIST1H3G,
SCARA5, HIST1H3H, HIST1H3I
Annotation Enrichment Score:
Cluster 37 0.8150571534515413
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051051~negative
7 0,037180608 INHBB, ADRB2, IL1B, NOS3, YRDC, NEDD4L, TACC3 48,31444976 BP ALL regulation of transport
GOTERM_ GO:0002028~regulation of
3 0,09227729 ADRB2, NOS3, NEDD4L 81,48211753 BP ALL sodium ion transport
GOTERM_ GO:0043271~negative
3 0,137566392 ADRB2, NOS3, NEDD4L 92,40701766 BP_ALL regulation of ion transport
GOTERM_ GO:0043269~regulation of
4 0,359722051 ADRB2, ATP4A, NOS3, NEDD4L 99,95762063 BP_ALL ion transport
GOTER _ GO:0010959~regulation of
3 0,495248889 ADRB2, NOS3, NEDD4L 99,99932712 BP ALL metal ion transport
Annotation Enrichment Score:
Cluster 38 0.7961397019020876
Gene
Category Term PValue Genes FDR
Count
BCL10, FGFRl, CEBPB, LOC100044206, LOC100045567,
GOTERM_ GO:0043066~negative
14 0,069876547 TGFBR1, PIM1, HSPAIA, HSPAIB, TIMPl, CASP4, BTG2, BAG 3, 71,68529685 BP_ALL regulation of apoptosis
BCL3, FAS, MKL1
GO:0043069~negative BCL10, FGFRl, CEBPB, LOC100044206, LOC100045567,
GOTERM_
regulation of programmed 14 0,D78S50116 TGFBR1, P1M1, HSPAIA, HSPAIB, TIMPl, CASP4, BTG2, BAG3, 75,94880258 BP_ALL
cell death BCL3, FAS, MKL1
BCL10, FGFRl, CEBPB, LOC100044206, LOC100045567,
GOTERM_ GO:0060548~negative
14 0,080796128 TGFBR1, PIM1, HSPAIA, HSPAIB, TIMPl, CASP4, BTG2, BAG3, 76,94979132 BP_ALL regulation of cell death
BCL3, FAS, MKL1
FGFRl, MCLl, LOC100044206, HSPAIA, HSPAIB, SOX9, TIMPl,
GOTERM_ GO:0042981~regulation of CASP4, BAG3, BCL3, TRP53INP1, SKIL, FAS, MKL1, TRAF3,
26 0,099401622 83,85703989 BP_ALL apoptosis B4GALT1, BCL10, CEBPB, LOC100045567, TGFBR1, PIM1,
BIRC2, BCL2L11, BRCA1, ADRB2, BTG2, RIPK2, CAMK1D
FGFRl, MCLl, LOC100044206, HSPAIA, HSPAIB, SOX9, TIMPl,
GOTERM_ GO:0043067~regulation of CASP4, BAG3, BCL3, TRP53INP1, SKIL, FAS, MKL1, TRAF3,
26 0,111754805 87,30889202 BP_ALL programmed cell death B4GALT1, BCL10, CEBPB, LOC100045567, TGFBR1, PIM1,
BIRC2, BCL2L11, BRCA1, ADRB2, BTG2, RIPK2, CAMK1D
FGFRl, MCLl, LOC100044206, HSPAIA, HSPAIB, SOX9, TIMPl,
GOTERM_ GO:0010941~regulation of CASP4, BAG3, BCL3, TRP53INP1, SKIL, FAS, MKL1, TRAF3,
26 0,116483604 88,4357324 BP_ALL cell death B4GALT1, BCL10, CEBPB, LOC100045567, TGFBR1, PIM1,
BIRC2, BCL2L11, BRCA1, ADRB2, BTG2, RIPK2, CAMK1D
GOTERM_ GO:0043065~positive B4GALT1, BCL10, CEBPB, LOC100044206, TGFBR1, BCL2L11,
12 0,234896119 99,05694238 BP ALL regulation of apoptosis BRCA1, ADRB2, CASP4, RIPK2, BCL3, TRP53INP1, FAS
GO:0043068~positive
GOTERM_ B4GALT1, BCL10, CEBPB, LOC100044206, TGFBR1, BCL2L11,
regulation of programmed 12 0,242704259 99,21125073 BP_ALL BRCA1, ADRB2, CASP4, RIPK2, BCL3, TRP53INP1, FAS
cell death
GOTERM_ GO:0010942~positive B4GALT1, BCL10, CEBPB, LOC100044206, TGFBR1, BCL2L11,
12 0,24878923 99,31465658 BP ALL regulation of cell death BRCA1, ADRB2, CASP4, RIPK2, BCL3, TRP53INP1, FAS LOC10O044206, FST, NFKB1, PAWR, CASP4, DYNLL1, ANG,
BAG3, IL1B, NOS3, FAS, MKL1, SERTAD1, EGR1, BCL10,
GTPBP4, SOCS3, PIMl, TLEl, MIDlIPl, SOCS5, INHBB, ADRB2,
GOTERM_ GO:0048523~negative
46 0,277890863 BTG2, BTG3, FGFR1, IFITM3, BEX1, HSPA1A, HSPA1B, SOX9, 99,65563574 BP_ALL regulation of cellular process
TIMP1, BCL3, SKIL, B4GALT1, IKZF4, CEBPB, LOC100045567,
TGFBR1, RCAN1, SMAD1, BRCA1, CYP7B1, LOC100048453,
RGS1, HOPX, WIF1, RBM15, CML2
GOTERM_ GO:0006917~induction of BCL10, CASP4, CEBPB, LOC100044206, TGFBR1, TRPS3INP1,
8 0,351508317 99,94708447 BP ALL apoptosis BCL3, FAS, BRCA1
GOTERM_ GO:0012502~induction of BCL10, CASP4, CEBPB, LOC100044206, TGFBR1, TRPS3INP1,
8 0,351508317 99,94708447 BP ALL programmed cell death BCL3, FAS, BRCA1
Annotation Enrichment Score:
Cluster 39 0.7778262933529285
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0042254~ribosome
9 0,039259684 RCLl, GTPBP4, TSRl, RRPIB, GARl, EMGl, BYSL, UTP6, GNL2 50,22445163 BP ALL biogenesis
GOTERM_ GO:0022613~ribonucleoprote RCLl, GTPBP4, TSRl, RRPIB, GARl, EMGl, CLPl, BYSL, UTP6,
10 0,04694351 56,72173009 BP ALL in complex biogenesis GNL2
GOTERM_
GO:0006364~rRNA processing 5 0,250027223 RCLl, RRPIB, GARl, EMGl, UTP6 99,33406632 BP ALL
GOTERM_ GO:0016072~rRNA metabolic
5 0,257599504 RCLl, RRPIB, GARl, EMGl, UTP6 99,44196474 BP ALL process
GOTERM GO:0034660~ncRNA
9 0,393122359 RCLl, TARS, RRPIB, GARl, EMGl, CLPl, INTS7, F13A1, UTP6 99,98333282 BP ALL metabolic process
GOTERM_ GO:0034470~ncRNA
7 0,461381118 RCLl, RRPIB, GARl, EMGl, CLPl, INTS7, UTP6 99,99791444 BP ALL processing
Annotation Enrichment Score:
Cluster 40 0.7339008607312588
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0031347~regulation of ADRB2, MYD88, LOC100048018, C3, RELA, TLR2, CFH, RIPK2,
8 0,064477752 68,6819415 BP ALL defense response LBP
GOTERM_ GO:0002673~regulation of
3 0,125822558 LOC100048018, C3, CFH, LBP 90,38986191 BP ALL acute inflammatory response
GOTERM_ GO:0032101~regulation of ADRB2, LOC640441, LOC100048018, C3, HOPX, CFH, LBP,
7 0,14382068 93,31113637 BP ALL response to external stimulus THBS1, CPB2
GOTERM_ GO:0050727~regulation of
4 0,312310432 ADRB2, LOC100048018, C3, CFH, LBP 99,85291909 BP ALL inflammatory response
GOTERM_ GO:0002697~regulation of
4 0,587380428 LOC100048018, C3, LOC100045567, CFH, LBP 99,9999799 BP ALL immune effector process
Annotation Enrichment Score:
Cluster 41 0.6863931298216815
Gene
Category Term PValue Genes FDR
Count
GOTERM_
GO:0042060~wound healing 8 0,09134954 B4GALT1, THBD, F10, FGA, F13A1, PROZ, HBEGF, FN1 81,14965895 BP ALL
GOTERM_ GO:0007596~blood
5 0,220268825 THBD, F10, FGA, F13A1, PROZ 98,68840485 BP ALL coagulation
GOTERM_
GO:0050817~coagulation 5 0,220268825 THBD, F10, FGA, F13A1, PROZ 98,68840485 BP ALL
GOTERM_
GO:0007599~hemostasis 5 0,2276207 THBD, F10, FGA, F13A1, PROZ 98,88792588 BP ALL
GOTERM_ GO:0050878~regulation of
5 0,366614943 THBD, F10, FGA, F13A1, PROZ 99,96490276 BP ALL body fluid levels
Annotation Enrichment Score:
Cluster 42 0.6749998245397322
Gene
Category Term PValue Genes FDR
Count EFNAl, HMGCR, LOC100046080, FST, TIRAP, LOC100044204,
SELENBP1, SERPINE2, GATA6, IL1B, FAS, SPRED1, EGFR, BCL10,
SOCS3, YY1, RE LA, RE LB, HES6, TACC3, GRHL1,
1100001G20RIK, JUNB, BCL2L11, AHR, TACC2, THBD, TAGLN,
CCR2, CD300LF, FGFRl, MCLl, MRAP, GRB2, ELL, NOC3L, BEXl,
HSPA1A, HSPA1B, SOX9, TIMP1, SLC11A2, ALCAM, FOXQ1,
SERPINA1B, SLC30A1, PPL, SKIL, RUNX1, LOC100043996,
GOTERM_ GO:0032502~developmental
109 0,06606342 GNATl, GINS1, B4GALT1, MAFF, SCD2, TGFBRl, CELSRl, 69,59382898 BP_ALL process
SMADl, CSRP2, BRCA1, GNAT2, CYP7B1, CXCL13, HOPX, WIF1,
CML2, STEAP4, SPIN1, NFKBl, LSR, ACVR1B, FOS, ALAS2, ANG,
NOS3, SIK1, EGR1, MMP19, TLE3, FMN2, SDCl, ADRB2, BTG2,
GADD45G, VCAN, SERP1, C6, CSF1, CCR1, TIPARP, HK2, LRG1,
XBP1, DHCR7, TGM1, KRT8, BCL3, ZC3H12A, ACSL4, ETV6,
PCSK5, CEBPB, RCANl, BIRC2, STAT3, GJB2, PLSCR1, PTP4A1,
GFRA1, HBEGF, CP, RBM15, CBS
EFNAl, FST, TIRAP, NFKBl, LSR, ACVR1B, ALAS2, GATA6, ANG,
IL1B, NOS3, FAS, EGR1, EGFR, BCL10, SOCS3, RELA, YY1, RELB,
MMP19, TACC3, JUNB, BCL2L11, AHR, TACC2, TAGLN, CCR2,
GADD45G, CD300LF, VCAN, SERP1, FGFRl, GRB2, CCR1, CSF1,
GOTERM_ GO:0048513~organ
69 0,0708724 TIPARP, HK2, SOX9, TIMP1, SLC11A2, FOXQ1, XBP1, DHCR7, 72,20874604 BP_ALL development
PPL, TGM1, KRT8, ZC3H12A, BCL3, SKIL, RUNX1, PCSK5,
B4GALT1, GNATl, CEBPB, TGFBRl, RCANl, CELSRl, SMADl,
BIRC2, STAT3, GNAT2, GJB2, CYP7B1, PLSCR1, CXCL13, HOPX,
HBEGF, RBM15, CBS
HMGCR, EFNAl, LOC100046080, FST, TIRAP, SERPINE2, GATA6,
IL1B, FAS, SPRED1, EGFR, BCL10, SOCS3, YY1, RELA, RELB,
HES6, GRHL1, TACC3, JUNB, BCL2L11, AHR, TACC2, THBD,
TAGLN, CCR2, CD300LF, FGFRl, MCLl, GRB2, ELL, BEXl,
HSPA1A, HSPA1B, SOX9, TIMP1, SLC11A2, ALCAM, FOXQ1,
SERPINA1B, SLC30A1, PPL, SKIL, RUNX1, LOC100043996,
GOTERM_ GO:0007275~multicellular
99 0,097869487 GNATl, GINS1, B4GALT1, MAFF, SCD2, TGFBRl, SMADl, 83,37192377 BP_ALL organismal development
CELSRl, CSRP2, BRCA1, GNAT2, CYP7B1, CXCL13, HOPX, WIF1,
CML2, SPIN1, NFKBl, LSR, ACVR1B, FOS, ALAS2, ANG, NOS3,
SIK1, EGR1, MMP19, TLE3, FMN2, BTG2, GADD45G, VCAN,
SERP1, CCR1, C6, CSF1, TIPARP, HK2, XBP1, DHCR7, TGM1,
KRT8, BCL3, ZC3H12A, ACSL4, PCSK5, CEBPB, RCANl, BIRC2,
STAT3, GJB2, PLSCR1, PTP4A1, GFRA1, HBEGF, RBM15, CBS
EFNAl, FST, TIRAP, NFKBl, LSR, ACVR1B, FOS, ALAS2,
SERPINE2, ANG, GATA6, IL1B, NOS3, FAS, EGR1, EGFR, BCL10,
SOCS3, RELA, YY1, RELB, MMP19, HES6, TACC3, JUNB, AHR,
BCL2L11, TACC2, BTG2, TAGLN, CCR2, GADD45G, CD300LF,
GOTERM_ GO:0048731~system VCAN, SERP1, FGFRl, GRB2, CCR1, CSF1, TIPARP, HK2, BEXl,
77 0,21894559 98,64908848 BP ALL development SOX9, TIMP1, SLC11A2, ALCAM, FOXQ1, XBP1, DHCR7, PPL,
TGM1, KRT8, ZC3H12A, BCL3, SKIL, RUNX1, PCSK5, B4GALT1,
GNATl, SCD2, CEBPB, TGFBRl, RCANl, CELSRl, SMADl, BIRC2,
STAT3, GJB2, GNAT2, CYP7B1, PLSCR1, CXCL13, HOPX, GFRA1,
HBEGF, RBM15, CBS
STEAP4, EFNAl, TIRAP, SELENBP1, LOC100044204, ALAS2,
SERPINE2, GATA6, ANG, FAS, SIK1, EGR1, SOCS3, RELB,
MMP19, TLE3, HES6, TACC3, 1100001G20RIK, JUNB, TACC2,
ADRB2, SDCl, BTG2, GADD45G, CD300LF, FGFRl, MCLl, GRB2,
GOTERM_ GO:0030154~cell
60 0,2439916 MRAP, CCR1, TIPARP, NOC3L, BEXl, HSPA1A, HSPA1B, SOX9, 99,23428305 BP_ALL differentiation
TIMP1, SLC11A2, ALCAM, XBP1, LRG1, DHCR7, PPL, TGM1,
KRT8, ZC3H12A, BCL3, SKIL, RUNX1, ETV6, B4GALT1, GNATl,
CEBPB, TGFBRl, RCANl, SMADl, CSRP2, STAT3, GNAT2,
PLSCR1, HOPX
EFNAl, FST, TIRAP, NFKBl, LSR, ACVR1B, FOS, ALAS2,
SERPINE2, ANG, GATA6, IL1B, NOS3, FAS, EGR1, EGFR, BCL10,
SOCS3, RELA, YY1, RELB, MMP19, HES6, TACC3, JUNB, AHR,
BCL2L11, TACC2, SDCl, BTG2, TAGLN, CCR2, GADD45G,
CD300LF, VCAN, SERP1, FGFRl, GRB2, CCR1, CSF1, TIPARP,
GOTERM_ GO:0048856~anatomical
81 0,264340695 HK2, BEXl, SOX9, TIMP1, SLC11A2, ALCAM, FOXQ1, XBP1, 99,52394588 BP_ALL structure development
DHCR7, PPL, TGM1, KRT8, ZC3H12A, BCL3, SKIL, RUNX1,
PCSK5, B4GALT1, GINS1, GNATl, SCD2, CEBPB, TGFBRl,
RCANl, CELSRl, SMADl, CSRP2, BIRC2, STAT3, GJB2, GNAT2,
CYP7B1, PLSCR1, CXCL13, HOPX, GFRA1, HBEGF, RBM15,
CML2, CBS STEAP4, EFNA1, TIRAP, LOC100044204, SELENBP1, ALAS2,
SERPINE2, GATA6, ANG, FAS, SIK1, EGR1, EGFR, SOCS3, RELB,
MMP19, TLE3, HES6, TACC3, 1100001G20RIK, JUNB, TACC2,
ADRB2, SDCl, BTG2, GADD45G, CD300LF, FGFRl, MCLl, GRB2,
GOTER _ GO:0048869~cellular
61 0,316461479 MRAP, CCRl, TIPARP, NOC3L, BEX1, HSPA1A, HSPA1B, SOX9, 99,86764073 BP_ALL developmental process
TIMPl, SLC11A2, ALCAM, XBP1, LRG1, DHCR7, PPL, TGM1,
KRT8, ZC3H12A, BCL3, SKIL, RUNX1, ETV6, B4GALT1, GNATl,
CEBPB, TGFBR1, RCAN1, SMAD1, CSRP2, STAT3, GNAT2,
PLSCRl, HOPX
FGFRl, EFNA1, GRB2, CSFl, TIPARP, FST, SOX9, ALCAM,
SLC11A2, FOXQ1, ANG, TGM1, KRT8, ZC3H12A, IL1B, NOS3,
GOTER _ GO:0009653~anatomical SKIL, PCSK5, B4GALT1, GNATl, EGFR, BCLIO, SOCS3, RELA, YYl,
41 0,411457444 99,99023245 BP_ALL structure morphogenesis TGFBR1, M P19, CELSR1, SMAD1, JUNB, BCL2L11, STAT3,
GNAT2, CYP7B1, HOPX, HBEGF, GFRA1, RBM15, CBS, CML2,
SERPl
EFNA1, HMGCR, LOC100046080, F13A1, MMP8, FST, TIRAP,
MYD88, SERPINE2, GATA6, PDE4B, IL1B, FAS, SPRED1, EGFR,
BCLIO, F10, SOCS3, YYl, RELA, RELB, HES6, TACC3, GRHL1,
JUNB, AHR, BCL2L11, TACC2, THBD, TAGLN, CCR2, CD300LF,
UNC13B, FGFRl, RAD23B, MCLl, ELL, GRB2, GLUD1, BEX1,
HSPA1A, HSPA1B, SOX9, TIMpi, SLC11A2, ALCAM, FOXQ1,
FGA, SERPINA1B, SLC30A1, PPL, SKIL, RUNX1, LOC100043996,
GOTERM_ GO:0032501~multicellular GNATl, GINS1, B4GALT1, MAFF, SCD2, AP2K3, TGFBR1,
121 0,998608344 100 BP_ALL organismal process CELSR1, SMAD1, CSRP2, BRCA1, GNAT2, CYP7B1, CXCL13,
HOPX, AVPR1A, WIF1, CML2, SPIN1, NFKB1, PAWR, LSR,
ACVR1B, FOS, ALAS2, ANG, IL1RAP, PROZ, NOS3, LBP, SIK1,
EGR1, MMP19, TLE3, FMN2, ADRB2, BTG2, GRM8, GADD45G,
VCAN, SERPl, PRTN3, C6, CREM, CSFl, CCRl, TIPARP, HK2, REL,
XBP1, DHCR7, TGM1, KRT8, BCL3, ZC3H12A, ACSL4, PCSK5,
B4GALNT1, CEBPB, RCAN1, BIRC2, STAT3, GJB2, IRF9, PLSCRl,
PTP4A1, GFRA1, HBEGF, RBM15, CBS
Annotation Enrichment Score:
Cluster 43 0.6550884847646185
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0030099~myeloid cell
8 0,047361171 SLC11A2, PLSCRl, ALAS2, CCRl, RELB, TIRAP, CD300LF, TIMPl 57,05091097 BP ALL differentiation
GOTERM_ GO:0048872~homeostasis of
7 0,193640942 SLC11A2, ALAS2, CSFl, FAS, SKIL, BCL2L11, TIMPl 97,64587539 BP ALL number of cells
GOTERM_ GO:0030218~erythrocyte
3 0,495248889 SLC11A2, ALAS2, TIMPl 99,99932712 BP ALL differentiation
GOTERM_ GO:0034101~erythrocyte
3 0,527719244 SLC11A2, ALAS2, TIMPl 99,99978869 BP ALL homeostasis
Annotation Enrichment Score:
Cluster 44 0.5603226172827197
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0048872~homeostasis of
7 0,193640942 SLC11A2, ALAS2, CSFl, FAS, SKIL, BCL2L11, TIMPl 97,64587539 BP ALL number of cells
GOTER _ GO:0002260~lymphocyte
3 0,276075953 FAS, SKIL, BCL2L11 99,64024446 BP ALL homeostasis
GOTERM_ GO:0001776~leukocyte
3 0,389947717 FAS, SKIL, BCL2L11 99,9817471 BP ALL homeostasis
Annotation Enrichment Score:
Cluster 45 0.5545882651119179
Gene
Category Term PValue Genes FDR
Count
GO:0045582~positive
GOTERM_
regulation of T cell 4 0,096251118 HSP90AA1, LOC100045567, RIPK2, SOCS5 82,84459858 BP_ALL
differentiation
GO:0045621~positive
GOTERM_
regulation of lymphocyte 4 0,110560615 HSP90AA1, LOC100045567, RIPK2, SOCS5 87,00838077 BP_ALL
differentiation
GOTER _ GO:0080135~regulation of
6 0,115619248 MYD88, LOC100045567, TIRAP, RIPK2, IL1B, CBS 88,23707347 BP ALL cellular response to stress
GO:0046638~positive
GOTERIVL regulation of alpha-beta T cell 3 0,137566392 LOC100045567, RIPK2, SOCS5 92,40701766 BP_ALL
differentiation
GOTER _ GO:0045619~regulation of
5 0,138318883 HSP90AA1, LOC100045567, RIPK2, FAS, SOCS5 92,52159556 BP ALL lymphocyte differentiation GO:0046637~regulation of
GOTERM_
alpha-beta T cell 3 0,174045679 LOC100045567, RIPK2, SOCS5 96,423436 BP_ALL
differentiation
GOTER _ GO:0050870~positive
5 0,191555725 BCLIO, HSP90AA1, LOC100045567, RIPK2, SOCS5 97,53755329 BP ALL regulation of T cell activation
GO:0051251~positive
GOTERM_
regulation of lymphocyte 6 0,222302201 BCLIO, YD88, HSP90AA1, LOC100045567, RIPK2, SOCS5 98,7467253 BP_ALL
activation
GO:0046635~positive
GOTERM_
regulation of alpha-beta T cell 3 0,224606914 LOC100045567, RIPK2, SOCS5 98,80987037 BP_ALL
activation
GOTERM_ GO:0051249~regulation of BCLIO, MYD88, HSP90AA1, LOC100045567, RIPK2, PAWR, FAS,
8 0,227367232 98,88155183 BP ALL lymphocyte activation SOCS5
GOTER _ GO:0045580~regulation of T
4 0,228019183 HSP90AA1, LOC100045567, RIPK2, SOCS5 98,89787753 BP ALL cell differentiation
GO:0002696~positive
GOTERM_
regulation of leukocyte 6 0,254294774 BCLIO, YD88, HSP90AA1, LOC100045567, RIPK2, SOCS5 99,39707746 BP_ALL
activation
GOTERM_ GO:00S0867~positive
6 0,267399601 BCLIO, MYD88, HSP90AA1, LOC100045567, RIPK2, SOCS5 99,5572736 BP ALL regulation of cell activation
GOTER _ GO:0002694~regulation of BCLIO, MYD88, HSP90AA1, LOC100045567, RIPK2, PAWR, FAS,
8 0,27972125 99,67052816 BP ALL leukocyte activation SOCS5
GOTERM_ GO:0050865~regulation of BCLIO, MYD88, HSP90AA1, LOC100045567, RIPK2, PAWR, FAS,
8 0,290548371 99,74693033 BP ALL cell activation SOCS5
GOTERM_ GO:0002819~regulation of
4 0,302827557 C3, LOC100045567, RIPK2, SOCS5 99,81329326 BP ALL adaptive immune response
GO:0002822~regulation of
adaptive immune response
based on somatic
GOTERM_
recombination of immune 4 0,302827557 C3, LOC100045567, RIPK2, SOCS5 99,81329326 BP_ALL
receptors built from
immunoglobulin superfamily
domains
GOTERM_ GO:0050863~regulation of T
6 0,31428335 BCLIO, HSP90AA1, LOC100045567, RIPK2, PAWR, SOCS5 99,8600986 BP ALL cell activation
GO:0002821~positive
GOTERM_
regulation of adaptive 3 0,327355039 C3, LOC100045567, RIPK2 99,8999491 BP_ALL
immune response
GO:0002824~positive
regulation of adaptive
immune response based on
GOTERM_
somatic recombination of 3 0,327355039 C3, LOC100045567, RIPK2 99,8999491 BP ALL
immune receptors built from
immunoglobulin superfamily
domains
GOTERM_ GO:0046634~regulation of
3 0,327355039 LOC100045567, RIPK2, SOCS5 99,8999491 BP ALL alpha-beta T cell activation
G0:0050671~positive
GOTER _
regulation of lymphocyte 3 0,517053772 MYD88, LOC100045567, RIPK2 99,99968821 BP_ALL
proliferation
GO:0032946~positive
GOTERM_
regulation of mononuclear 3 0,517053772 MYD88, LOC100045567, RIPK2 99,99968821 BP_ALL
cell proliferation
GOTERM_ GO:0050670~regulation of
4 0,522521196 MYD88, LOC100045567, RIPK2, PAWR 99,9997443 BP ALL lymphocyte proliferation
GO:0032944~regulation of
GOTERM_
mononuclear cell 4 0,522521196 MYD88, LOC100045567, RIPK2, PAWR 99,9997443 BP_ALL
proliferation
GO:0070665~positive
GOTERM_
regulation of leukocyte 3 0,538224086 MYD88, LOC100045567, RIPK2 99,99985719 BP ALL
proliferation
GOTER _ GO:0070663~regulation of
4 0,53925913 MYD88, LOC100045567, RIPK2, PAWR 99,99986266 BP ALL leukocyte proliferation
GOTERM_ GO:0050864~regulation of B
3 0,568760461 LOC100045567, PAWR, FAS 99,99995663 BP ALL cell activation
GOTERM_ GO:0042129~regulation of T
3 0,607162546 LOC100045567, RIPK2, PAWR 99,99999146 BP ALL cell proliferation
Annotation Enrichment Score:
Cluster 46 0.5512876507434779
Gene
Category Term PValue Genes FDR
Count HIST2H3C2, HIST2H3C1, LOC100045728, LOC100044416, FGA,
GO:0034622~cellular ANG, CLPl, TUBB6, TUBA1A, TUBA1B, TUBA1C, HIST2H3B,
GOTER _
macromolecular complex 14 0,037249193 TSRl, LOC100045490, H2AFY3, HIST1H3A, H2AFY2, HIST1H3B, 48,37854428 BP_ALL
assembly HIST1H3C, H3F3A, HIST1H3D, H3F3B, HIST1H3E, HIST1H3F,
UNC13B, HIST1H3G, HIST1H3H, HIST1H3I
HIST2H3C2, HIST2H3C1, LOC100045728, LOC100044416, FGA,
GO:0034621~cellular ANG, CLPl, TUBB6, TUBA1A, TUBA1B, TUBA1C, HIST2H3B,
GOTERM_
macromolecular complex 14 0,080796128 TSRl, LOC100045490, H2AFY3, HIST1H3A, H2AFY2, HIST1H3B, 76,94979132 BP_ALL
subunit organization HIST1H3C, H3F3A, HIST1H3D, H3F3B, HIST1H3E, HIST1H3F,
UNC13B, HIST1H3G, HIST1H3H, HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HIST2H3C1, H2AFY3,
GOTERM_ GO:0006334~nucleosome H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
5 0,242503972 99,20760915 BP_ALL assembly HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H,
HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HIST2H3C1, H2AFY3,
GOTERM_ GO:0031497~chromatin H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
5 0,257599504 99,44196474 BP_ALL assembly HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H,
HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HIST2H3C1, H2AFY3,
GOTERM_ GO:0065004~protein-DNA H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
5 0,265216822 99,5337256 BP_ALL complex assembly HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H,
HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HIST2H3C1, H2AFY3,
GOTER _ GO:0034728~nucleosome H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
5 0,265216822 99,5337256 BP_ALL organization HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H,
HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HIST2H3C1, H2AFY3,
GOTERM_ H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
GO:0006323~DNA packaging 5 0,459762174 99,99780251 BP_ALL HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H,
HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HIST2H3C1, H2AFY3,
GOTER _ GO:0006333~chromatin H2AFY2, HIST1H3A, HIST1H3B, H3F3A, HIST1H3C, H3F3B,
5 0,519227025 99,99971176 BP_ALL assembly or disassembly HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H,
HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HIST2H3C1, H2AFY3,
GOTERM_ GO:0006325~chromatin H2AFY2, HIST1H3A, HOPX, HIST1H3B, H3F3A, HIST1H3C,
6 0,985219127 100 BP ALL organization H3F3B, HIST1H3D, HIST1H3E, HIST1H3F, HIST1H3G, HIST1H3H,
HIST1H3I
HIST2H3B, LOC100045490, HIST2H3C2, HSPA1A, HIST2H3C1,
GOTERM_ GO:0051276~chromosome HSPA1B, H2AFY3, H2AFY2, HIST1H3A, HOPX, HIST1H3B,
8 0,987021714 100 BP_ALL organization H3F3A, HIST1H3C, H3F3B, FBX04, HIST1H3D, HIST1H3E,
HIST1H3F, HIST1H3G, HIST1H3H, HIST1H3I
Annotation Enrichment Score:
Cluster 47 0.4914105699441552
Gene
Category Term PValue Genes FDR
Count
CSTF3, APOBEC1, EMG1, GAR1, SNRPD3, TRA2A, UTP6,
GOTER _
GO:0006396~RNA processing 19 0,247320294 SYNCRIP, HNRNPA1, RCL1, PAPOLA, RRPIB, CLPl, INTS7, 99,29093435 BP ALL PABPCl, RBM39, CWC22, ZCCHC6, RBM25
APOBEC1, GAR1, ELL, SNRPD3, F13A1, UTP6, TRA2A, SYNCRIP,
GOTER _ GO:0016070~RNA metabolic RRPIB, DNAJB11, ANG, CLPl, INTS7, PABPCl, ZCCHC6, RBM25,
27 0,260460929 99,47826751 BP_ALL process CSTF3, EMG1, GTF2B, HNRNPA1, AHR, STAT3, RCL1, TARS,
PAPOLA, RBM39, CWC22
GOTERM_ GO:0006397~mRNA CSTF3, PAPOLA, APOBEC1, SNRPD3, CLPl, TRA2A, SYNCRIP,
12 0,291415387 99,75226384 BP ALL processing PABPCl, RBM39, CWC22, HNRNPA1, RBM25
GOTERM_ GO:0016071~mRNA CSTF3, APOBEC1, SNRPD3, TRA2A, SYNCRIP, HNRNPA1,
13 0,344032864 99,93539165 BP ALL metabolic process PAPOLA, DNAJB11, CLPl, RBM39, PABPCl, CWC22, RBM25
GOTERM_ SNRPD3, CLPl, TRA2A, SYNCRIP, PABPCl, RBM39, CWC22,
GO:0008380~RNA splicing 8 0,540545678 99,99986919 BP ALL HNRNPA1
Annotation Enrichment Score:
Cluster 48 0.45547222211638627
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0001655~urogenital
8 0,237566145 FGFR1, CYP7B1, TGFBR1, TIPARP, SOX9, PCSK5, BCL2L11, AHR 99,11265542 BP ALL system development
GOTER _ GO:0030850~prostate gland
3 0,389947717 CYP7B1, SOX9, AHR 99,9817471 BP ALL development
GOTERM_ GO:0048608~reproductive
6 0,464293284 CYP7B1, FST, NOS3, SOX9, BCL2L11, AHR 99,99810238 BP ALL structure development Annotation Enrichment Score:
Cluster 49 0.44777016759041594
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051186~cofactor SLC11A2, ALDHILI, ALAS2, HMGCR, ACNAT2, ADH4, KMO,
10 0,175911389
BP ALL 96,5615825 metabolic process ACLY, LOC100044878, DCXR
GOTERM_ GO:0006732~coenzyme
7 0,369249866 ALDHILI, HMGCR, ACNAT2, KMO, ACLY, LOC100044878, DCXR 99,96736101 BP ALL metabolic process
GOTERM_ GO:0051188~cofactor
5 0,382323043 SLC11A2, ALAS2, KMO, ACLY, LOC100044878 99,97733815 BP_ALL biosynthetic process
GOTERM_ GO:0009108~coenzyme
3 0,651440195 KMO, ACLY, LOC100044878 99,99999894 BP ALL biosynthetic process
Annotation Enrichment Score:
Cluster 50 0.4469809447691943
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0019935~cyclic-
5 0,191555725 GNATl, ADRB2, RAPGEF4, SLC9A3R1, GNAT2 97,53755329 BP ALL nucleotide-mediated signaling
GO:0019932~second-
GOTER _
messenger-mediated 7 0,220708616 GNATl, ADRB2, AVPRIA, RAPGEF4, RCANl, SLC9A3R1, GNAT2 98,70123147 BP_ALL
signaling
GO:0007187~G-protein
GOTERM_
signaling, coupled to cyclic 3 0,616348123 GNATl, ADRB2, GNAT2 99,99999434 BP_ALL
nucleotide second messenger
GOTERM_ GO:0019933~cAMP-mediated
3 0,625368094 ADRB2, RAPGEF4, SLC9A3R1 99,99999626 BP ALL signaling
Annotation Enrichment Score:
Cluster 51 0.43867411137638873
Gene
Category Term PValue Genes FDR
Count
GO:0009968~negative
GOTERM_
regulation of signal 9 0,236147619 CYP7B1, ADRB2, RGSl, SOCS3, ILIB, WIFl, PAWR, SKIL, SOCS5 99,08345466 BP ALL
transduction
GO:0010648~negative
GOTERM_
regulation of cell 9 0,310012308 CYP7B1, ADRB2, RGSl, SOCS3, ILIB, WIFl, PAWR, SKIL, SOCS5 99,84411846 BP_ALL
communication
GO:0048585~negative
GOTERM_
regulation of response to 3 0,659804326 ADRB2, SOCS3, ILIB 99,9999993 BP_ALL
stimulus
Annotation Enrichment Score:
Cluster 52 0.3964917151946916
Gene
Category Term PValue Genes FDR
Count
GO:0010SS2~positive
GOTER _ regulation of specific
3 0,19913203 GATA6, NFKB1, RBM15 97,91003935 BP_ALL transcription from RNA
polymerase II promoter
GO:0043193~positive
GOTERM_
regulation of gene-specific 3 0,3651833 GATA6, NFKB1, RBM15 99,96349497 BP_ALL
transcription
GO:0010551~regulation of
GOTERM_
specific transcription from 3 0,527719244 GATA6, NFKB1, RBM15 99,99978869 BP ALL RNA polymerase II promoter
GOTERM_ GO:0032583~regulation of
3 0,676049004 GATA6, NFKB1, RBM15 99,9999997 BP_ALL gene-specific transcription
Annotation Enrichment Score:
Cluster 53 0.3873489768178085
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0000041~transition metal
7 0,033013732 SLC11A2, SLC39A14, STEAP4, SLC30A1, CP, SLC39A4, SCARA5 44,2765634 BP ALL ion transport
GOTERM_ GO:0006826~iron ion
4 0,096251118 SLC11A2, SLC39A14, STEAP4, SCARA5 82,84459858 BP ALL transport
GOTERM_ GO:0015674~di-, tri-valent
5 0,808965945 SLC11A2, SLC39A14, STEAP4, ATP2A2, SCARA5 100 BP ALL inorganic cation transport
GOTERM_ GO:0030001~metal ion SLC11A2, SLC39A14, STEAP4, SLC38A2, ATP2A2, ATP4A,
12 0,898711735 100 BP_ALL transport SLC30A1, SLC10A6, CP, SLC10A2, SLC39A4, SCARA5 STEAP4, SLC39A14, SLC38A2, ATP4A, SLC10A6, SLC10A2,
G0TERM_
GO:0006812~cation transport 14 0,905341301 SLC11A2, ATP2A2, SLC30A1, SLC41A2, SLC41A1, CP, SLC39A4, 100 BP_ALL
SCARA5
STEAP4, SLC39A14, CLCA2, CLCA1, SLC38A2, ATP4A, SLC22A7,
GOTER _
GO:0006811~ion transport 19 0,93521952 SLC10A6, SLC10A2, SLC11A2, ANK, SLC01A1, ATP2A2, 100 BP_ALL
SLC30A1, SLC41A2, SLC41A1, CP, SLC39A4, SCARA5
GOTERM_ GO:0015672~monovalent
5 0,993528236 SLC11A2, SLC38A2, ATP4A, SLC10A6, SLC10A2 100 BP_ALL inorganic cation transport
Annotation Enrichment Score:
Cluster 54 0.38597869291841375
Gene
Category Term PValue Genes FDR
Count
GOTERM_ G0:0007017~microtubule- F N2, DYNLL1, TUBB6, TUBA1A, TACC3, LOC100045728,
10 0,301553929 99,80726199 BP ALL based process GADD45A, TUBAIB, BRCA1, TUBA1C, TACC2, LOC100044416
GOTER _ GO:0000226~microtubule FMN2, TACC3, GADD45A, TUBAIB, BRCA1, TACC2,
6 0,334713873 99,91739554 BP ALL cytoskeleton organization LOC100044416
GOTERM_ GO:0007010~cytoskeleton FMN2, TAGLN, ANG, SVIL, S100A9, TACC3, GADD45A, TUBAIB,
11 0,688692283 99,99999985 BP ALL organization BRCA1, TACC2, SYNPO, LOC100044416
Annotation Enrichment Score:
Cluster 55 0.37911731600595844
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051249~regulation of BCLIO, MYD88, HSP90AA1, LOC100045567, RIPK2, PAWR, FAS,
8 0,227367232 98,88155183 BP ALL lymphocyte activation SOCS5
GOTERM_ GO:0002694~regulation of BCLIO, MYD88, HSP90AA1, LOC100045567, RIPK2, PAWR, FAS,
8 0,27972125 99,67052816 BP ALL leukocyte activation SOCS5
GOTERM_ GO:0050865~regulation of BCLIO, MYD88, HSP90AA1, LOC100045567, RIPK2, PAWR, FAS,
8 0,290548371 99,74693033 BP_ALL cell activation SOCS5
GO:0051250~negative
GOTERM_
regulation of lymphocyte 3 0,538224086 PAWR, FAS, SOCS5 99,99985719 BP_ALL
activation
GO:0002695~negative
GOTERM_
regulation of leukocyte 3 0,548566714 PAWR, FAS, SOCS5 99,99990375 BP_ALL
activation
GOTER _ GO:0050866~negative
3 0,548566714 PAWR, FAS, SOCS5 99,99990375 BP ALL regulation of cell activation
GO:0002683~negative
GOTERM_
regulation of immune system 3 0,741455298 PAWR, FAS, SOCS5 99,99999999 BP_ALL
process
Annotation Enrichment Score:
Cluster 56 0.3647078743395495
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0035295~tube B4GALT1, FGFR1, BCLIO, GATA6, DHCR7, CSF1, HOPX, NOS3,
12 0,300929664 99,80423916 BP ALL development CELSR1, PCSK5, RBM15, BCL2L11
GOTERM_ GO:0030323~respiratory tube
6 0,348399344 FGFR1, GATA6, DHCR7, HOPX, NOS3, PCSK5 99,94248727 BP ALL development
GOTER _ GO:0030324~lung
5 0,533614959 FGFR1, GATA6, DHCR7, HOPX, NOS3 99,99983022 BP ALL development
GOTERM_ GO:0060541~respiratory
5 0,621438533 FGFR1, GATA6, DHCR7, HOPX, NOS3 99,99999552 BP ALL system development
Annotation Enrichment Score:
Cluster 57 0.33964339158607365
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0031399~regulation of
8 0,340289769 EGFR, BCLIO, GTPBP4, SOCS3, TIRAP, FBX04, RAPGEF4, CBS 99,92865999 BP ALL protein modification process
EGFR, BCLIO, GTPBP4, SOCS3, RELA, TI AP, UBE2L6,
GOTER _ GO:0051246~regulation of
14 0,430898289 LOC100048018, ANG, CFH, FBX04, RAPGEF4, SERP1, ADAM9, 99,994559 BP_ALL protein metabolic process
CBS
GO:0032268~regulation of
GOTERM_ EGFR, BCLIO, GTPBP4, ANG, S0CS3, TIRAP, FBX04, RAPGEF4,
cellular protein metabolic 11 0,496050969 99,99934551 BP_ALL ADAM9, CBS, SERP1
process
GO:0001932~regulation of
GOTER _
protein amino acid 5 0,602110872 EGFR, S0CS3, TIRAP, RAPGEF4, CBS 99,99998933 BP_ALL
phosphorylation Annotation Enrichment Score:
Cluster 58 0.31641785202512046
Gene
Category Term PValue Genes FDR
Count
GO:0001754~eye
GOTERM_
photoreceptor cell 3 0,186528999 GNAT1, STAT3, GNAT2 97,25679507 BP_ALL
differentiation
GOTERM_ GO:0046530~photoreceptor
3 0,250303577 GNAT1, STAT3, GNAT2 99,33832778 BP ALL cell differentiation
GOTERM_ GO:0048592~eye
4 0,461483214 GNAT1, YY1, STAT3, GNAT2 99,99792132 BP ALL morphogenesis
GOTERM_ GO:0007423~sensory organ
8 0,785332036 GNAT1, FGFR1, YY1, CELSR1, SKIL, BCL2L11, STAT3, GNAT2 100 BP ALL development
GOTERM_ GO:0001654~eye
5 0,793155619 GNAT1, YY1, SKIL, STAT3, GNAT2 100 BP ALL development
GOTERM_ GO:0043010~camera-type
3 0,941264859 YY1, SKIL, GNAT2 100 BP ALL eye development
Annotation Enrichment Score:
Cluster 59 0.29844300146199076
Gene
Category Term PValue Genes FDR
Count
RAD23B, A2M, SPIN1, LOC100046080, CREM, CSF1, FST, HK2,
GOTERM_ HSPAIA, HSPAIB, SOX9, ARG1, NOS3, ACSL4, PCSK5,
GO:0000003~reproduction 26 0,240120224 99,16303368 BP_ALL B4GALNT1, B4GALT1, TGFBR1, TLE3, SMADl, BCL2L11, AHR,
STAT3, JUNB, GJB2, CYP7B1, FMN2, THBD
RAD23B, A2M, SPIN1, LOC100046080, CREM, CSF1, FST, HK2,
GOTERM_ GO:0022414~reproductive HSPAIA, HSPAIB, SOX9, ARG1, NOS3, ACSL4, PCSK5,
25 0,301776279 99,80832799 BP_ALL process B4GALNT1, B4GALT1, TGFBR1, TLE3, SMADl, BCL2L11, AHR,
JUNB, GJB2, CYP7B1, FMN2, THBD
GO:0048609~reproductive B4GALT1, RAD23B, SPIN1, CREM, TGFBR1, LOC100046080,
GOTERM_
process in a multicellular 16 0,435247264 FST, TLE3, HK2, HSPAIA, HSPAIB, SMADl, JUNB, BCL2L11, 99,99523956 BP_ALL
organism FMN2, NOS3, ACSL4, B4GALNT1
B4GALT1, RAD23B, SPIN1, CREM, TGFBR1, LOC100046080,
GOTERM_ GO:0032504~multicellular
16 0,435247264 FST, TLE3, HK2, HSPAIA, HSPAIB, SMADl, JUNB, BCL2L11, 99,99523956 BP_ALL organism reproduction
FMN2, NOS3, ACSL4, B4GALNT1
B4GALT1, RAD23B, SPIN1, CREM, TGFBR1, LOC100046080,
GOTERM_ GO:0019953~sexual
14 0,571032056 FST, TLE3, HSPAIA, HSPAIB, SMADl, STAT3, BCL2L11, FMN2, 99,99996044 BP_ALL reproduction
NOS3, B4GALNT1
GOTERM_ GO:0007276~gamete RAD23B, SPIN1, CREM, TGFBR1, LOC100046080, FST, TLE3,
12 0,589629746 99,99998172 BP ALL generation HSPAIA, HSPAIB, SMADl, BCL2L11, FMN2, NOS3, B4GALNT1
GOTERM_ GO:0048232~male gamete
6 0,941488647 RAD23B, CREM, TLE3, HSPAIA, HSPAIB, BCL2L11, B4GALNT1 100 BP ALL generation
GOTERM_ GO:0007283~spermatogenesi
6 0,941488647 RAD23B, CREM, TLE3, HSPAIA, HSPAIB, BCL2L11, B4GALNT1 100 BP ALL s
Annotation Enrichment Score:
Cluster 60 0.29640849277816717
Gene
Category Term PValue Genes FDR
Count
GO:0044271~nitrogen HSP90AA1, ATP4A, LOC100045567, ATPllA, ASNS, KMO,
GOTERM_
compound biosynthetic 18 0,032141842 PSPH, GUCY2C, AG XT, SLC11A2, ARG1, CTH, ALAS2, ATP2A2, 43,39486997 BP_ALL
process HDC, ADK, NOS3, CBS
ALDH1L1, ATP4A, LOC100045567, HAL, ATPllA, GUCY2C,
GOTERM_ GO:0046483~heterocycle
15 0,11988576 LOC100044878, MOXD1, AFMID, SLC11A2, TD02, ALAS2, 89,18736275 BP_ALL metabolic process
ATP2A2, HDC, ADK
GO:0009145~purine
GOTERM_
nucleoside triphosphate 5 0,405795211 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA 99,98845967 BP_ALL
biosynthetic process
GO:0009142~nucleoside
GOTERM_
triphosphate biosynthetic 5 0,413583894 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA 99,99082928 BP ALL
process
GO:0055086~nucleobase,
GOTERM_ ATP2A2, ATP4A, PNP2, HMGCR, LOC100045567, ADK, ATPllA,
nucleoside and nucleotide 11 0,455208115 99,99745651 BP_ALL KMO, GNMT, GUCY2C, DCXR
metabolic process
GO:0009144~purine
GOTERM_
nucleoside triphosphate 5 0,497265103 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA 99,99937244 BP_ALL
metabolic process
GO:0006164~purine
GOTERM_
nucleotide biosynthetic 6 0,510434134 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA, GUCY2C 99,99960477 BP ALL
process
GOTERM_ GO:0009165~nucleotide
7 0,555478413 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA, KMO, GUCY2C 99,99992643 BP ALL biosynthetic process GO:0009141~nucleoside
GOTERM_
triphosphate metabolic 5 0,56173064 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA 99,99994252 BP ALL
process
GO:0034654~nucleobase,
GOTERM_ nucleoside, nucleotide and
7 0,583325366 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA, KMO, GUCY2C 99,99997616 BP_ALL nucleic acid biosynthetic
process
GO:0034404~nucleobase,
GOTERM_
nucleoside and nucleotide 7 0,583325366 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA, KMO, GUCY2C 99,99997616 BP_ALL
biosynthetic process
GOTERM_ GO:0009117~nucleotide ATP2A2, ATP4A, HMGCR, LOC100045567, ADK, ATPllA, KMO,
9 0,618771299 99,99999493 BP ALL metabolic process GUCY2C, DCXR
GOTERM_ GO:0006753~nucleoside ATP2A2, ATP4A, HMGCR, LOC100045567, ADK, ATPllA, KMO,
9 0,618771299 99,99999493 BP ALL phosphate metabolic process GUCY2C, DCXR
GO:0009206~purine
GOTERM_
ribonucleoside triphosphate 4 0,6249393 ATP2A2, ATP4A, LOC100045567, ATPllA 99,99999619 BP_ALL
biosynthetic process
GO:0009201~ribonucleoside
GOTERM_
triphosphate biosynthetic 4 0,6249393 ATP2A2, ATP4A, LOC100045567, ATPllA 99,99999619 BP_ALL
process
GOTERM_ GO:0006163~purine
6 0,64828475 ATP2A2, ATP4A, LOC100045567, ADK, ATPllA, GUCY2C 99,99999876 BP ALL nucleotide metabolic process
GO:0009205~purine
GOTERM_
ribonucleoside triphosphate 4 0,680009 ATP2A2, ATP4A, LOC100045567, ATPllA 99,99999976 BP_ALL
metabolic process
GO:0009199~ribonucleoside
GOTERM_
triphosphate metabolic 4 0,686453394 ATP2A2, ATP4A, LOC100045567, ATPllA 99,99999983 BP_ALL
process
GO:0009152~purine
GOTERM_
ribonucleotide biosynthetic 4 0,717219955 ATP2A2, ATP4A, LOC100045567, ATPllA 99,99999997 BP_ALL
process
GOTERM_ GO:0009260~ribonucleotide
4 0,740110118 ATP2A2, ATP4A, LOC100045567, ATPllA 99,99999999 BP_ALL biosynthetic process
GOTERM_ GO:0006754~ATP
3 0,778512986 ATP2A2, ATP4A, ATPllA 100 BP_ALL biosynthetic process
GO:OO0915O~purine
GOTERM_
ribonucleotide metabolic 4 0,78145601 ATP2A2, ATP4A, LOC100045567, ATPllA 100 BP_ALL
process
GOTERM_ GO:0009259~ribonucleotide
4 0,808782534 ATP2A2, ATP4A, LOC100045567, ATPllA 100 BP ALL metabolic process
GOTERM_ GO:0046034~ATP metabolic
3 0,820642837 ATP2A2, ATP4A, ATPllA 100 BP ALL process
Annotation Enrichment Score:
Cluster 61 0.2797502504159065
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0007548~sex
6 0,464293284 B4GALT1, FST, NOS3, SOX9, BCL2L11, GJB2 99,99810238 BP ALL differentiation
GOTERM_ GO:0048608~reproductive
6 0,464293284 CYP7B1, FST, NOS3, SOX9, BCL2L11, AHR 99,99810238 BP ALL structure development
GOTERM_ GO:0045137~development of
5 0,482389706 FST, NOS3, SOX9, BCL2L11, GJB2 99,99895709 BP ALL primary sexual characteristics
GO:0046546~development of
GOTERIVL
primary male sexual 3 0,548566714 SOX9, BCL2L11, GJB2 99,99990375 BP_ALL
characteristics
GOTERM_ GO:0003006~reproductive B4GALT1, CYP7B1, CSF1, FST, IMOS3, SOX9, BCL2L11, JUNB,
10 0,558499104 99,99993467 BP ALL developmental process AHR, GJB2
GOTERM_ GO:0008406~gonad
4 0,587380428 FST, NOS3, SOX9, BCL2L11 99,9999799 BP ALL development
GOTERM_ GO:0046661~male sex
3 0,588293442 SOX9, BCL2L11, GJB2 99,99998066 BP ALL differentiation
Annotation Enrichment Score:
Cluster 62 0.2782990915616783
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0010817~regulation of
6 0,450864996 CYP17A1, RBP1, SERPINA6, IL1RN, RAPGEF4, PCSK5 99,99707922 BP ALL hormone levels
GOTERM_ GO:0034754~cellular
3 0,538224086 CYP17A1, RBP1, SERPINA6 99,99985719 BP ALL hormone metabolic process
Figure imgf000115_0001
APOBEC1, DPH5, EFNA1, F13A1, TIRAP, ST3GAL1, ACVRIB,
MAP3K5, EROILB, DNAJB11, ISG15, MAP3K8, SIK1, EGFR,
PIM1, PI 3, BD1, LOC100044878, BTG2, GADD45G, RIPK2,
GOTERM_ GO:0043412~biopolymer SERP1, CAMK1D, FGFR1, TIPARP, ABCA1, RIOK2, STT3A,
50 0,315935694 99,86585604 BP ALL modification SERPINAIB, SERPINAIA, TGMl, DUSP16, SERPINAIC, FBX04,
NEDD4L, QSOXl, B4GALT1, ST6GAL1, B3GALT1, PTPN2, CES6,
TGFBR1, MAP2K3, UBE2L6, GUCY2C, PTPN12, IKBKE, PTP4A1,
HOPX, PTPN1
FGFR1, EFNA1, DPH5, F13A1, TIPARP, TIRAP, ABCA1, RIOK2,
ST3GAL1, ACVRIB, MAP3K5, EROILB, STT3A, ISG15,
SERPINAIB, SERPINAIA, TGMl, DUSP16, SERPINAIC, MAP3K8,
G0TERM_ GO:0006464~protein
47 0,358492143 FBX04, NEDD4L, SIK1, QSOXl, B4GALT1, EGFR, ST6GAL1, 99,95618004 BP_ALL modification process
B3GALT1, PTP , CES6, MAP2K3, TGFBR1, PIM1, UBE2L6,
PIM3, GUCY2C, LOC100044878, PTPN12, IKBKE, BTG2, PTP4A1,
GADD45G, HOPX, RIPK2, PTPN1, SERP1, CAMK1D
EFNA1, DPH5, F13A1, TIRAP, ST3GAL1, ACVRIB, HSPH1,
EROILB, MAP3K5, DNAJB11, ISG15, MAP3K8, RPL12, SIK1,
EGFR, HSP90AA1, SOCS3, PIM1, PIM3, SOCS5, EIF1A,
LOC100044878, GTF2B, TARS, BTG2, GADD45G, RIPK2,
FKBP11, CAMK1D, SERP1, RAD23B, FGFR1, FKBP5, TIPARP,
GOTERM_ GO:0044267~cellular protein
72 0,562013592 RFFL, ABCA1, RIOK2, EDEM1, PCOLCE, RPL30, STT3A, 99,99994316 BP_ALL metabolic process
SERPINAIB, SERPINAIA, DUSP16, SERPINAIC, TGMl, RPL3,
FBX04, NEDD4L, QSOXl, B4GALT1, ST6GAL1, B3GALT1, PTPN2,
CES6, MAP2K3, TGFBR1, SPSB4, UBE2L6, GUCY2C, BRCA1,
PTPN12, WSB1, IKBKE, PPID, PTP4A1, SPCS3, HOPX, SPCS2,
PTPN1, DNAJB1, DNAJB4
FGFR1, EFNA1, F13A1, TIPARP, TIRAP, RIOK2, ACVRIB,
GO:0043687~post- MAP3K5, EROILB, ISG15, MAP3K8, DUSP16, TGMl, FBX04,
GOTERM_
translational protein 33 0,797593572 SIK1, QSOXl, EGFR, PTPN2, MAP2K3, TGFBR1, PIM1, UBE2L6, 100 BP_ALL
modification PIM3, GUCY2C, PTPN12, IKBKE, BTG2, PTP4A1, GADD45G,
HOPX, RIPK2, PTPN1, CAMK1D
FGFR1, MVD, EFNA1, HK2, TIRAP, RIOK2, ACVRIB, MAP3K5,
G0TERM_ GO:0006796~phosphate MAP3K8, DUSP16, SIK1, EGFR, PTPN2, TGFBR1, MAP2K3,
26 0,845765177 100 BP_ALL metabolic process PIM1, PIM3, GUCY2C, PTPN12, PPA1, IKBKE, PTP4A1,
GADD45G, RIPK2, PTPN1, CAMK1D
FGFR1, MVD, EFNA1, HK2, TIRAP, RIOK2, ACVRIB, MAP3K5,
GOTERM_ GO:0006793~phosphorus MAP3K8, DUSP16, SIK1, EGFR, PTPN2, TGFBR1, MAP2K3,
26 0,845765177 100 BP_ALL metabolic process PIM1, PIM3, GUCY2C, PTPN12, PPA1, IKBKE, PTP4A1,
GADD45G, RIPK2, PTPN1, CAMK1D
EGFR, FGFR1, EFNA1, TGFBR1, MAP2K3, TIRAP, PIM1, PIM3,
GOTERM_ GO:0006468~protein amino
18 0,892958803 GUCY2C, RIOK2, IKBKE, ACVRIB, MAP3K5, MAP3K8, GADD45G, 100 BP_ALL acid phosphorylation
RIPK2, SIK1, CAMK1D
EGFR, FGFR1, MVD, EFNA1, MAP2K3, TGFBR1, HK2, TIRAP,
GOTERM
GO:0016310~phosphorylation 20 0,907603793 PIM1, PIM3, GUCY2C, RIOK2, ACVRIB, IKBKE, MAP3K5, 100 BP_ALL
MAP3K8, GADD45G, RIPK2, SIK1, CAM KID
Annotation Enrichment Score:
Cluster 68 0.20450556720482063
Gene
Category Term PValue Genes FDR
Count
GO:0032268~regulation of
GOTERM_ EGFR, BCL10, GTPBP4, ANG, SOCS3, TIRAP, FBX04, RAPGEF4,
cellular protein metabolic 11 0,496050969 99,99934551 BP_ALL ADAM9, CBS, SERP1
process
GO:0032270~positive
GOTERM_
regulation of cellular protein 4 0,673467015 BCL10, FBX04, ADAM9, SERP1 99,99999966 BP_ALL
metabolic process
GO:0051247~positive
GOTERM_
regulation of protein 4 0,728854209 BCL10, FBX04, ADAM9, SERP1 99,99999999 BP_ALL
metabolic process
Annotation Enrichment Score:
Cluster 69 0.18381844767746208
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006351~transcription,
5 0,608619132 ELL, ANG, GTF2B, STAT3, AHR 99,99999199 BP ALL DNA-dependent
GOTERM_ GO:0032774~RNA
5 0,633990958 ELL, ANG, GTF2B, STAT3, AHR 99,99999751 BP ALL biosynthetic process
GO:0006366~transcription
GOTERM_
from RNA polymerase II 3 0,727974208 ELL, STAT3, AHR 99,99999999 BP ALL
promoter Annotation Enrichment Score:
Cluster 70 0.18238891897548448
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0051640~organelle
4 0,283909406 FMN2, SYNE1, TACC3, TACC2 99,70235222 BP ALL localization
GOTERM_ GO:0000226~microtubule FMN2, TACC3, GADD45A, TUBA1B, BRCA1, TACC2,
6 0,334713873 99,91739554 BP ALL cytoskeleton organization LOC100044416
CKS1B, SPIN1, S100A6, LOC100046080, PIM1, NEDD9, PI 3,
GOTER _
GO:0007049~cell cycle 17 0,898605648 TACC3, AHR, BRCA1, TACC2, F N2, PTP4A1, MAP3K8, 100 BP ALL TRP53INP1, SKIL, SIK1, GADD45A
GOTERM_ GO:0022402~cell cycle FMN2, SPIN1, LOC100046080, NEDD9, TRP53INP1, SKIL,
9 0,963236658 100 BP ALL process TACC3, GADD45A, BRCA1, TACC2
GOTERM_
GO:0000279~M phase 5 0,989047221 F N2, SPIN1, LOC100046080, NEDD9, TACC3, TACC2 100 BP ALL
GOTERM_ F N2, SPIN1, LOC100046080, NEDD9, TACC3, GADD45A,
GO:0022403~cell cycle phase 6 0,989222119 100 BP ALL TACC2
Annotation Enrichment Score:
Cluster 71 0.14S80329004639808
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048729~tissue EGFR, BCL10, CYP7B1, FOXQ1, CSF1, FST, CELSRl, SMAD1,
9 0,576722756 99,99996865 BP ALL morphogenesis SOX9
GOTERM_ GO:0035239~tube
6 0,704826661 B4GALT1, BCL10, CSF1, CELSRl, RBM15, BCL2L11 99,99999994 BP ALL morphogenesis
GOTERM_ GO:0002009~morphogenesis
6 0,714395634 EGFR, BCL10, CYP7B1, CSF1, CELSRl, SOX9 99,99999997 BP ALL of an epithelium
GOTERM_ GO:0060562~epithelial tube
3 0,899080621 BCL10, CSF1, CELSRl 100 BP ALL morphogenesis
Annotation Enrichment Score:
Cluster 72 0.1449208407887165
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0021987~cerebral cortex
3 0,3651833 EGFR, TACC3, TACC2 99,96349497 BP ALL development
GOTERM_ GO:0021543~pallium
3 0,548566714 EGFR, TACC3, TACC2 99,99990375 BP ALL development
GOTERM_ GO:0021537~telencephalon
3 0,713902817 EGFR, TACC3, TACC2 99,99999997 BP ALL development
GOTERM_ GO:0007417~central nervous
8 0,972529869 EGFR, FGFR1, ANG, CELSRl, SMAD1, RUNX1, TACC3, TACC2 100 BP ALL system development
GOTER _ GO:0030900~forebrain
3 0,98036545 EGFR, TACC3, TACC2 100 BP ALL development
GOTERM_ GO:0007420~brain
5 0,990386137 EGFR, FGFR1, S AD1, TACC3, TACC2 100 BP ALL development
Annotation Enrichment Score:
Cluster 73 0.08647841687183509
Gene
Category Term PValue Genes FDR
Count
S100A4, PVR, STEAP4, APOBEC1, HIP1R, S100A9, TLR2,
VPS37C, LOC100044204, SELENBP1, LSR, AGXT, SLC7A7,
CXCL10, SLC1A4, ANK, ER01LB, STARD4, SERPINA6, APOF,
LCAT, ILIB, CSF3R, RAPGEF4, LBP, RAB20, EGFR, CLCA2, CLCAl,
ATP4A, SLC22A7, CMAH, TACC3, MCART1, TACC2, FMN2,
ADRB2, TNS1, RAB18, SLC41A2, SLC41A1, UNC13B, SEC61G,
GOTERM_
GO:0051179~localization 88 0,717668888 SNXIO, SERPl, SLC39A14, SLC38A2, RBPl, CCRl, AKAP12, RFFL, 99,99999997 BP ALL ABCAl, ABCA3, SLC02A1, SLC11A2, LOC100045000, SLCOlAl,
SLC35B3, SLC30A1, DOPEY2, SLC39A4, B4GALNT1, B4GALT1,
LCN13, OSBPL9, RRBP1, TGFBR1, SYT11, MUP3, SYT12, IL1RN,
SLC10A6, ATPllA, CELSRl, SLC10A2, HNRNPAl, CYB561, LCN2,
RAB32, SLC35C1, ORM1, SYNE1, NOLC1, ATP2A2, HBEGF, CP,
SCARA5, SLC25A15, ORM2, OR 3 S100A4, STEAP4, APOBEC1, HIP1R, TLR2, VPS37C,
LOC100044204, SELENBP1, LSR, AGXT, SLC7A7, CXCL10,
SLC1A4, ANK, ER01LB, STARD4, SERPINA6, APOF, LCAT,
RAPGEF4, LBP, RAB20, CLCA2, CLCAl, ATP4A, SLC22A7, CMAH,
MCART1, FMN2, ADRB2, RAB18, SLC41A2, SLC41A1, UNC13B,
GOTERM_ GO:0051234~establishment SNX10, SEC61G, SERP1, SLC39A14, SLC38A2, RBP1, AKAP12,
74 0,856619404 100 BP_ALL of localization RFFL, ABCAl, ABCA3, SLC02A1, SLC11A2, LOC100045000,
SLCOlAl, SLC35B3, SLC30A1, DOPEY2, SLC39A4, LCN13,
OSBPL9, RRBPl, MUP3, SYT11, SYT12, IL1RN, SLC10A6,
ATP11A, SLC10A2, CYB561, HNRNPA1, LCN2, ORM1, SLC35C1,
RAB32, SYNE1, NOLC1, ATP2A2, CP, SCARA5, SLC25A15,
ORM2, ORM3
S100A4, STEAP4, APOBEC1, HIP1R, TLR2, VPS37C,
LOC100044204, SELENBP1, LSR, AGXT, SLC7A7, CXCL10,
SLC1A4, ANK, ER01LB, STARD4, SERPINA6, APOF, LCAT,
RAPGEF4, LBP, RAB20, CLCA2, CLCAl, ATP4A, SLC22A7, CMAH,
MCART1, ADRB2, RAB18, SLC41A2, SLC41A1, UNC13B, SNX10,
GOTERM_
GO:0006810~transport 72 0,895061181 SEC61G, SERP1, SLC39A14, SLC38A2, RBP1, AKAP12, RFFL, 100 BP_ALL
ABCAl, ABCA3, SLC02A1, SLC11A2, LOC100045000, SLCOlAl,
SLC35B3, SLC30A1, DOPEY2, SLC39A4, LCN13, OSBPL9, RRBPl,
MUP3, SYT11, SYT12, IL1RN, SLC10A6, ATP11A, SLC10A2,
CYB561, HNRNPA1, LCN2, ORM1, SLC35C1, RAB32, NOLC1,
ATP2A2, CP, SCARA5, SLC25A15, ORM2, ORM3
Annotation Enrichment Score:
Cluster 74 0.08026706640961886
Gene
Category Term PValue Genes FDR
Count
GO:0051130~positive
GOTERM_
regulation of cellular 4 0,795499379 C3, TGFBR1, AHR, SY PO 100 BP_ALL
component organization
GO:0044087~regulation of
GOTERM_
cellular component 3 0,815799412 TGFBR1, AHR, SYNPO 100 BP ALL
biogenesis
GO:0051128~regulation of
GOTERM_ C3, EFNA1, TGFBR1, S100A9, FERMT2, MID1IP1, AHR, FN1,
cellular component 9 0,885065817 100 BP_ALL SYNPO
organization
Annotation Enrichment Score:
Cluster 75 0.07080101985545381
Gene
Category Term PValue Genes FDR
Count
RAD23B, FOXA3, TIRAP, TREX1, HSPA1A, HSPA1B, RAD52,
GOTERM_ GO:0033554~cellular
14 0,637059068 BRCA1, MYD88, BTG2, AVPR1A, BCL3, SCARA5, GADD45A, 99,99999785 BP ALL response to stress
SERP1
GOTERM_ GO:0006974~response to RAD23B, BTG2, BCL3, TREX1, HSPA1A, HSPA1B, RAD52,
8 0,868497689 100 BP ALL DNA damage stimulus GADD45A, BRCA1
GOTERM_
GO:0006281~DNA repair 5 0,950000812 RAD23B, TREX1, HSPA1A, HSPA1B, RAD52, BRCA1 100 BP ALL
GOTERM_ GO:0006259~DNA metabolic GINS1, RAD23B, TREX1, HSPA1A, FBX04, HSPA1B, RAD52,
8 0,991113917 100 BP ALL process MBD1, BRCA1
Annotation Enrichment Score:
Cluster 76 0.0573288477005333
Gene
Category Term PValue Genes FDR
Count
GO:0031327~negative
GOTERM_ EGR1, IKZF4, GTPBP4, NFKB1, TLE1, SOX9, BRCA1, INHBB,
regulation of cellular 14 0,722367888 99,99999998 BP_ALL DYNLL1, ANG, HOPX, BCL3, SKIL, RBM15
biosynthetic process
GO:0009890~negative
GOTER _ EGR1, IKZF4, GTPBP4, NFKB1, TLE1, SOX9, BRCA1, INHBB,
regulation of biosynthetic 14 0,73429725 99,99999999 BP_ALL DYNLL1, ANG, HOPX, BCL3, SKIL, RBM15
process
GO:0009892~negative
GOTERM_ EGR1, IKZF4, GTPBP4, RELA, NFKB1, TLE1, SOX9, BRCA1,
regulation of metabolic 17 0,750211602 100 BP_ALL INHBB, DYNLL1, ANG, CLP1, HOPX, IL1B, BCL3, SKIL, RBM15
process
GO:0010558~negative
GOTERM_ EGR1, INHBB, IKZF4, GTPBP4, ANG, HOPX, BCL3, NFKB1, TLEl,
regulation of macromolecule 12 0,85622237 100 BP_ALL SKIL, SOX9, RBM15
biosynthetic process
GO:0031324~negative
GOTERM_ EGR1, IKZF4, GTPBP4, NFKB1, TLEl, SOX9, BRCA1, INHBB,
regulation of cellular 14 0,864375637 100 BP ALL DYIMLLl, ANG, HOPX, BCL3, SKIL, RBM15
metabolic process GO:0010605~negative
GOTERM_ EGRl, IKZF4, GTPBP4, RELA, TLEl, NFKBl, SOX9, INHBB, ANG,
regulation of macromolecule 14 0,892486321 100 BP ALL CLPl, HOPX, BCL3, SKIL, RB 15
metabolic process
GO:0045892~negative
GOTER _
regulation of transcription, 8 0,909337562 EGRl, IKZF4, HOPX, NFKBl, TLEl, SKIL, SOX9, RBM15 100 BP_ALL
DNA-dependent
GO:0051253~negative
GOTER _
regulation of RNA metabolic 8 0,912592062 EGRl, IKZF4, HOPX, NFKBl, TLEl, SKIL, SOX9, RBM15 100 BP_ALL
process
GO:0051172~negative
GOTERM EGRl, IKZF4, GTPBP4, DYNLLl, HOPX, NFKBl, TLEl, SKIL, SOX9,
regulation of nitrogen 10 0,937258661 100 BP_ALL RBM15
compound metabolic process
GO:0000122~negative
GOTER _ regulation of transcription
5 0,959657239 EGRl, HOPX, TLEl, SKIL, RBM15 100 BP_ALL from RNA polymerase II
promoter
GO:0045934~negative
regulation of nucleobase,
GOTERM_
nucleoside, nucleotide and 9 0,965989372 EGRl, IKZF4, GTPBP4, HOPX, NFKBl, TLEl, SKIL, SOX9, RBM15 100 BP_ALL
nucleic acid metabolic
process
GOTERM_ GO:0010629~negative
9 0,97369728 EGRl, IKZF4, CLPl, HOPX, NFKBl, TLEl, SKIL, SOX9, RBM15 100 BP ALL regulation of gene expression
GOTERM_ GO:0016481~negative
8 0,97419632 EGRl, IKZF4, HOPX, NFKBl, TLEl, SKIL, SOX9, RB 1S 100 BP ALL regulation of transcription
Annotation Enrichment Score:
Cluster 77 0.05511585030610224
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0008654~phospholipid
3 0,784216983 ISYNA1, PLD1, LPGAT1 100 BP ALL biosynthetic process
GOTERM_ GO:0006644~phospholipid
4 0,922703014 ISYNA1, PLD1, LPGAT1, GATA6 100 BP ALL metabolic process
GOTERM_ GO:0019637~organophosphat
4 0,944396278 ISYNA1, PLD1, LPGAT1, GATA6 100 BP ALL e metabolic process
Annotation Enrichment Score:
Cluster 78 0.05115234106451917
Gene
Category Term PValue Genes FDR
Count
GO:0003001~generation of a
GOTER _
signal involved in cell-cell 3 0,789791636 IL1RN, RAPGEF4, UNC13B 100 BP_ALL
signaling
GOTER _ LOC100045000, IL1RN, RAPGEF4, ABCA1, UNC13B, AGXT,
GO:0046903~secretion 6 0,881355528 100 BP ALL CXCL10
GOTERM_ GO:0007267~cell-cell
7 0,93708222 FGFR1, GRM8, IL1RN, RAPGEF4, CELSR1, UNC13B, GJB2 100 BP ALL signaling
GOTER _
GO:0032940~secretion by cell 4 0,957082279 LOC100045000, IL1RN, RAPGEF4, UNC13B, CXCL10 100 BP ALL
Annotation Enrichment Score:
Cluster 79 0.045872409345646646
Gene
Category Term PValue Genes FDR
Count
GO:0035023~regulaticn of
GOTERM_
Rho protein signal 3 0,800561431 TIA 2, FGD6, FARP1 100 BP_ALL
transduction
GO:0046578~regulation of
GOTERM_
Ras protein signal 4 0,951121268 TIAM2, CSF1, FGD6, FARP1 100 BP ALL
transduction
GO:0051056~regulation of
GOTERM_
small GTPase mediated signal 5 0,956648106 TIAM2, CSF1, RAPGEF4, FGD6, FARP1 100 BP_ALL
transduction
Annotation Enrichment Score:
Cluster 80 0.045084702994418815
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0007611~learning or
4 0,595081549 EGRl, SLC11A2, HMGCR, GLUD1 99,99998552 BP_ALL memory
Figure imgf000120_0001
APOBEC1, RRBP1, AKAP12, VPS37C, LOC100044204,
G0TERM_ GO:0008104~protein
17 0,988210653 SELENBPl, RFFL, CELSRl, TACC3, LSR, CXCLIO, LOC100045000, 100 BP_ALL localization
RAB32, RAB18, DOPEY2, RAB20, SEC61G, SNX10, SERP1
Annotation Enrichment Score:
Cluster 84 0.028715811990451305
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009952~anterior/posteri
4 0,901023382 BTG2, TGFBR1, YY1, PCSK5 100 BP ALL or pattern formation
GOTER _ GO:0007389~pattern
7 0,929038868 BTG2, TGFBR1, YY1, FST, S AD1, PCSK5, RBM1S 100 BP ALL specification process
GOTER _
GO:0003002~regionalization 4 0,979676339 BTG2, TGFBR1, YY1, PCSK5 100 BP ALL
Annotation Enrichment Score:
Cluster 85 0.026632250344064842
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0010324~membrane
5 0,891543497 ADRB2, HIP1R, ABCA1, LBP, SCARA5 100 BP ALL invagination
GOTER _
GO:0006897~endocytosis 5 0,891543497 ADRB2, HIP1R, ABCA1, LBP, SCARA5 100 BP ALL
GOTERM_ GO:0016044~membrane
5 0,98545 ADRB2, HIP1R, ABCA1, LBP, SCARA5 100 BP ALL organization
GOTER _ GO:0016192~vesicle-
7 0,998967436 ADRB2, HIP1R, RAPGEF4, ABCA1, LBP, UNC13B, SCARA5 100 BP ALL mediated transport
Annotation Enrichment Score:
Cluster 86 0.005032010489871343
Gene
Category Term PValue Genes FDR
Count
GOTERM_
GO:0032940~secretion by cell 4 0,957082279 LOC100045000, ILIRN, RAPGEF4, UNC13B, CXCLIO 100 BP ALL
GOTER _ GO:0051641~cellular ILIRN, AKAP12, RFFL, TACC3, HNRNPAl, CXCLIO, TACC2,
12 0,998352059 100 BP ALL localization LOC100045000, FMN2, SYNEl, RAPGEF4, UNC13B, SEC61G
GOTERM_ GO:0051649~establishment FMN2, LOC100045000, SYNEl, ILIRN, A AP12, RAPGEF4, RFFL,
10 0,999200509 100 BP ALL of localization in cell UNC13B, HNRNPAl, SEC61G, CXCLIO
GOTERM_ GO:0046907~intracellular
4 0,999968498 AKAP12, RFFL, HNRNPAl, SEC61G 100 BP ALL transport
Annotation Enrichment Score:
Cluster 87 0.004348672248756842
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048666~neuron
6 0,974526015 ALCA , SLC11A2, GNAT1, FGFR1, RUNX1, GNAT2 100 BP ALL development
GOTERM_ GO:0031175~neuron
3 0,995930242 ALCAM, SLC11A2, FGFR1 100 BP ALL projection development
GOTERM_ GO:0030030~cell projection
3 0,999842575 ALCAM, SLC11A2, FGFR1 100 BP ALL organization
Annotation Enrichment Score:
Cluster 88 0.004194457559158197
Gene
Category Term PValue Genes FDR
Count
GO:0000904~cell
GOTER _
morphogenesis involved in 4 0,978540382 ALCAM, SLC11A2, KRT8, SOX9 100 BP_ALL
differentiation
GOTER _ GO:0000902~cell
5 0,994485933 ALCAM, EGFR, SLC11A2, KRT8, SOX9 100 BP ALL morphogenesis
GOTERM_ GO:0032989~cellular
5 0,998249797 ALCAM, EGFR, SLC11A2, KRT8, SOX9 100 BP ALL component morphogenesis
Annotation Enrichment Score:
Cluster 89 1.3663056923925995E-4
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0006886~intracellular
3 0,999360292 AKAP12, RFFL, SEC61G 100 BP ALL protein transport
GOTERM_ GO:0034613~cellular protein
3 0,999696968 AKAP12, RFFL, SEC61G 100 BP ALL localization
Figure imgf000122_0001
Table IV
Figure imgf000123_0001
GOTERM_ GO:0006637~acyl-CoA metabolic
4 4,54E-04 ACOT2, ACOTl, ACOT4, ACOT3 0,6787726 BP ALL process
GOTERM_ GO:0051186~cofactor metabolic
8 4,98E-04 AC02, HMGCR, PDK4, ACOT2, ACOTl, ACLY, ACOT4, ACOT3 0,7445804 BP ALL process
GOTERM_ GO:0006084~acetyl-CoA
3 0,0234295 AC02, PDK4, ACLY 29,908505 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 4 2.805478506657421
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0006720~isoprenoid
7 l,89E-06 MVD, HMGCR, FDPS, IDI1, RDH16, FDFT1, RETSAT 0,0028328 BP ALL metabolic process
GOTERM_ GO:0006721~terpenoid metabolic
3 0,0206602 IDI1, RDH16, RETSAT 26,869401 BP ALL process
GOTERM_ GO:0019748~secondary
3 0,0981712 IDI1, RDH16, RETSAT 78,750544 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 5 2.416841827871017
Gene
Category Term PValue Genes FDR
Count
CYB5R3, STEAP4, KLK1B4, HMGCR, TIRAP, ACOT2, PRDX4,
ACOTl, LSS, PMVK, ACOT4, FDFT1, SC4MOL, ACOT3, PTER,
GOTERM_
GO:0008152~metabolic process 81 2,53E-07 APOA4, USP18, P4HA2, CYP7A1, SULT1A1, VNN1, NQ02, 3,79E-04 BP_ALL
EGFR, AC02, PIM1, PNPLA2, DECR1, HES6, EIF1A, PIGP,
MBDl, G6PC, CD36, NNT, BTG2, SQLE, CYP4A31, HSD1
CYB5R3, HMGCR, KLK1B4, ACOT2, TIRAP, ACOTl, LSS, PMVK,
ACOT4, ACOT3, SC4MOL, FDFT1, USP18, P4HA2, CYP7A1,
GOTERM_ GO:0044238~primary metabolic
60 0,0177604 SULT1A1, EGFR, PIM1, PNPLA2, HES6, EIF1A, PIGP, MBDl, 23,555554 BP_ALL process
G6PC, BTG2, CYP4A31, HSD17B11, LOC100048346, ENPP5,
CYP51, FRK, ECH1, HSD17B2, MVD, FKBP5, CHKB
HMGCR, ACOT2, TIRAP, ACOTl, ACOT4, ACOT3, SC4MOL,
FDFT1, AP0A4, USP18, P4HA2, EGFR, AC02, PIM1, PNPLA2,
GOTERM_ GO:0044237~cellular metabolic
54 0,0694791 HES6, EIF1A, MBDl, PIGP, G6PC, CD36, BTG2, CYP4A31, 66,019415 BP_ALL process
ENPP5, LOC100048346, FRK, ECH1, MVD, FKBP5, CHKB,
CREM, DCI, HADHB, SBK1, FM02, PLA2G12A, TGM1, PAB
STEAP4, HMGCR, TIRAP, PRDX4, ACOT2, ACOTl,
LOC100044204, SELENBPl, ACOT4, FDFT1, ACOT3, SC4MOL,
GOTERM_
GO:0009987~cellular process 70 0,6901227 APOA4, ARHGAP6, USP18, P4HA2, DYNLL1, DYNLL2, VNN1, 99,999998 BP_ALL
EGFR, AC02, SLC22A7, PIM1, PNPLA2, HES6, EIF1A, PIGP,
MBDl, G6PC, CD36, BTG2, CYP4A31, SEC61G, LOC100048346
Annotation Enrichment Score:
Cluster 6 1.0895266997806818
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0046486~glycerolipid
5 0,017313 G6PC, CHKB, PNPLA2, PIGP, FABP5 23,031953 BP ALL metabolic process
GOTERM_ GO:0046474~glycerophospholipid
3 0,0484376 CHKB, PIGP, FABP5 52,48914 BP ALL biosynthetic process
GOTERM_ GO:0045017~glycerolipid
3 0,0729586 CHKB, PIGP, FABP5 67,874956 BP ALL biosynthetic process
GOTERM_ GO:0006644~phospholipid
4 0,1297935 CHKB, PLA2G12A, PIGP, FABP5 87,555166 BP ALL metabolic process
GOTERM_ GO:0008654~phospholipid
3 0,1331369 CHKB, PIGP, FABP5 88,252906 BP ALL biosynthetic process
GOTER _ GO:0006650~glycerophospholipid
3 0,1462307 CHKB, PIGP, FABP5 90,649136 BP ALL metabolic process
GOTER _ GO:0019637~organophosphate
4 0,1527891 CHKB, PLA2G12A, PIGP, FABP5 91,669842 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 7 0.9964377269616563
Gene
Category Term PValue Genes FDR
Count
STEAP4, AQP8, LOC100044204, SELENBPl, APOA4, SLC01A4,
GOTERM_ STARD4, DYNLL2, GLRX, SLC22A7, ATP11A, CRAT, CYB561,
GO:0006810~transport 25 0,0788775 70,815816 BP_ALL ORMl, G6PC, LYVEl, CD36, RAB30, NNT, SLC16A7, SLC41A2,
RAB17, SLC6A6, FABP2, FABP5, SEC61G
Figure imgf000125_0001
GOTERM_ GO:0044262~cellular
4 0,4598994 G6PC, PDK4, ACLY, FABP5 99,990227 BP ALL carbohydrate metabolic process
GOTERM_ GO:0005975~carbohydrate
5 0,4611662 LYVEl, G6PC, PDK4, ACLY, FABP5 99,990565 BP ALL metabolic process
Annotation Enrichment Score:
Cluster 12 0.2834911793804048
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0042325~regulation of
4 0,3842884 EGFR, KLK1B4, HMGCR, TIRAP 99,930347 BP ALL phosphorylation
GOTERM_ GO:0019220~regulation of
4 0,4070855 EGFR, KLK1B4, HMGCR, TIRAP 99,960432 BP ALL phosphate metabolic process
GOTERM_ GO:0051174~regulation of
4 0,4070855 EGFR, KLK1B4, HMGCR, TIRAP 99,960432 BP ALL phosphorus metabolic process
GOTERM_ GO.0043549~regulation of kinase
3 0,4343864 KLK1B4, HMGCR, TIRAP 99,98048 BP_ALL activity
GOTERM_ GO:0051338~regulation of
3 0,4525573 KLK1B4, HMGCR, TIRAP 99,988035 BP ALL transferase activity
GOTERM_ GO:0043085~positive regulation
3 0,597744 ARHGAP6, KLK1B4, TIRAP 99,999882 BP ALL of catalytic activity
GOTERM_ GO:0044093~positive regulation
3 0,6839961 ARHGAP6, KLK1B4, TIRAP 99,999997 BP ALL of molecular function
GOTER _ GO:0050790~regulation of
4 0,6924694 ARHGAP6, KLK1B4, HMGCR, TIRAP 99,999998 BP ALL catalytic activity
GOTERM_ GO:0065009~regulation of
4 0,7925592 ARHGAP6, KLK1B4, HMGCR, TIRAP 100 BP ALL molecular function
Annotation Enrichment Score:
Cluster 13 0.24250790750143128
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0043412~biopolymer EGFR, LOC100048346, FRK, PDK4, TIRAP, PIMl, UBE2L6, PIGP,
13 0,3112173 99,6259 BP ALL modification MBDl, USP18, SBKl, P4HA2, BTG2, TGMl
GOTER _ GO:0006464~protein modification EGFR, LOC100048346, FRK, PDK4, PIMl, TIRAP, UBE2L6, PIGP,
12 0,3720474 99,906439 BP ALL process USP18, SBKl, BTG , P4HA2, TGMl
GOTERM_ GO:0043687~post-translational LOC100048346, EGFR, FRK, USP18, BTG2, SBKl, TGMl, PDK4,
10 0,4200709 99,971609 BP ALL protein modification TIRAP, PIMl, UBE2L6
GOTERM_
GO:0016310~phosphorylation 7 0,474311 EGFR, FRK, MVD, SBKl, PDK4, TIRAP, PIMl 99,993484 BP ALL
GOTERM_ GO:0006793~phosphorus
8 0,498653 EGFR, FRK, G6PC, MVD, SBKl, PDK4, TIRAP, PIMl 99,996799 BP ALL metabolic process
GOTERM_ GO:0006796~phosphate
8 0,498653 EGFR, FRK, G6PC, MVD, SBKl, PDK4, TIRAP, PIMl 99,996799 BP ALL metabolic process
GOTERM_ GO:0006468~protein amino acid
6 0,5472224 EGFR, FRK, SBKl, PDK4, TIRAP, PIMl 99,999305 BP_ALL phosphorylation
EGFR, LOC100048346, FRK, FKBP5, PDK4, TIRAP, PIMl,
GOTERM_ GO:0044267~cellular protein
15 0,7464705 UBE2L6, SPSB4, EIFIA, PIGP, USP18, BTG2, SBKl, P4HA2, 100 BP_ALL metabolic process
TGMl
EGFR, LOC100048346, FRK, FKBP5, KLK1B4, PDK4, TIRAP,
GOTERM_ GO:0019538~protein metabolic
16 0,9199171 PIMl, UBE2L6, SPSB4, EIFIA, PIGP, USP18, BTG2, SBKl, 100 BP_ALL process
P4HA2, TGMl
LOC100048346, FRK, FKBP5, CREM, TIRAP, APOA4, USP18,
GOTERM_ GO:0044260~cellular P4HA2, SBKl, TGMl, PABPC1, EGFR, PDK4, PIMl, SPSB4,
23 0,9979027 100 BP_ALL macromolecule metabolic process UBE2L6, EIFIA, HES6, PIGP, MBDl, CYP4A10, G6PC, CD36,
BTG2, CYP4A31
LOC100048346, FRK, KLK1B4, FKBP5, CREM, TIRAP, APOA4,
GOTERM_ GO:0043170~macromolecule USP18, P4HA2, SBKl, TGMl, PABPC1, EGFR, PDK4, PIMl,
25 0,9994359 100 BP_ALL metabolic process SPSB4, UBE2L6, EIFIA, HES6, PIGP, MBDl, CYP4A10, LYVEl,
G6PC, CD36, BTG2, CYP4A31
Annotation Enrichment Score:
Cluster 14 0.23452556358999765
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009117~nucleotide
3 0,5675891 ENPP5, HMGCR, ATP11A 99,999651 BP ALL metabolic process
GOTERM_ GO:0006753~nucleoside
3 0,5675891 ENPP5, HMGCR, ATP11A 99,999651 BP ALL phosphate metabolic process GO:0055086~nucleobase,
G0TERM_
nucleoside and nucleotide 3 0,6142642 ENPP5, HMGCR, ATP11A 99,999937 BP_ALL
metabolic process
Annotation Enrichment Score:
Cluster 15 0.17355401710605015
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0043066~negative regulation
3 0,5496506 BTG2, PIM1, VNN1 99,999359 BP ALL of apoptosis
GOTER _ GO:0043069~negative regulation
3 0,5609221 BTG2, PIM1, VNN1 99,999561 BP_ALL of programmed cell death
GOTERM_ GO:0060548~negative regulation
3 0,5631524 BTG2, PIM1, VNN1 99,999594 BP_ALL of cell death
GOTERM_ GO:0042981~regulation of
5 0,6171804 BTG2, PIM1, VNN1, TRAF3, CIDEC 99,999944 BP ALL apoptosis
GOTERM_ GO:0043067~regulation of
5 0,6271312 BTG2, PIM1, VNN1, TRAF3, CIDEC 99,999962 BP ALL programmed cell death
GOTERM_ GO:0010941~regulation of cell
5 0,6313464 BTG2, PI 1, VNN1, TRAF3, CIDEC 99,999968 BP ALL death
GOTERM_ GO:0048519~negative regulation
6 0,9788719 BTG2, DYNLL1, PI 1, VNN1, PNPLA2, MID1IP1 100 BP ALL of biological process
GOTERM_ GO:0048523~negative regulation
5 0,9844384 BTG2, DYNLL1, PIM1, VNN1, MID1IP1 100 BP ALL of cellular process
Annotation Enrichment Score:
Cluster 16 0.15009020645890664
Gene
Category Term PValue Genes FDR
Count
GOTER _ GO:0033036~macromolecule APOA4, STARD4, CD36, RAB30, RAB17, ATP11A,
8 0,5425251 99,999189 BP ALL localization LOC100044204, SELENBPl, SEC61G
GOTER _
GO:0015031~protein transport 5 0,7412597 CD36, RAB30, RAB17, LOC100044204, SELENBPl, SEC61G 100 BP ALL
GOTERM_ GO:0045184~establishment of
5 0,7466976 CD36, RAB30, RAB17, LOC100044204, SELENBPl, SEC61G 100 BP ALL protein localization
GOTER _
GO:0008104~protein localization 5 0,8358035 CD36, RAB30, RAB17, LOC100044204, SELENBPl, SEC61G 100 BP ALL
Annotation Enrichment Score:
Cluster 17 0.06391091783429381
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0009057~macromolecule
6 0,5667131 LOC100048346, LYVEl, G6PC, USP18, CD36, UBE2L6, SPSB4 99,999641 BP ALL catabolic process
GOTERM_ GO:0044265~cellular
4 0,8514558 LOC100048346, USP18, CD36, UBE2L6, SPSB4 100 BP_ALL macromolecule catabolic process
GO:0019941~modification-
GOTERM_
dependent protein catabolic 3 0,9053393 LOC100048346, USP18, UBE2L6, SPSB4 100 BP_ALL
process
GO:0043632~modification-
GOTERM_
dependent macromolecule 3 0,9053393 LOC100048346, USP18, UBE2L6, SPSB4 100 BP_ALL
catabolic process
GO:0051603~proteolysis involved
GOTERM_
in cellular protein catabolic 3 0,9198096 LOC100048346, USP18, UBE2L6, SPSB4 100 BP_ALL
process
GOTERM_ GO:0044257~cellular protein
3 0,9213399 LOC100048346, USP18, UBE2L6, SPSB4 100 BP_ALL catabolic process
GOTERM_ GO:0030163~protein catabolic
3 0,9304167 LOC100048346, USP18, UBE2L6, SPSB4 100 BP ALL process
GOTERM
GO:0006508~proteolysis 4 0,988028 LOC100048346, USP18, KLK1B4, UBE2L6, SPSB4 100 BP ALL
Annotation Enrichment Score:
Cluster 18 0.005648647769130303
Gene
Category Term PValue Genes FDR
Count
GOTERM_ GO:0048869~cellular PEX11A, EGFR, STEAP4, BTG2, DHCR7, TG 1, TIRAP,
9 0,9434143 100 BP ALL developmental process LOC100044204, SELENBPl, HES6
GOTER _ GO:0007399~nervous system
4 0,9630927 EGFR, BTG2, GFRA1, HES6 100 BP ALL development G0TERM_ PEXllA, STEAP4, BTG2, DHCR7, TGM1, TIRAP,
GO:0030154~cell differentiation 8 0,9636756 100 BP_ALL LOC100044204, SELENBP1, HES6
G0TERM_ GO:0048731~system
8 0,9967861 EGFR, BTG2, DHCR7, CHKB, TGM1, TIRAP, GFRAl, HES6 100 BP ALL development
GOTERM_ GO:0032502~developmental EGFR, STEAP4, HMGCR, CHKB, TIRAP, SELENBP1,
12 0,9970342 100 BP_ALL process LOC100044204, HES6, PEXllA, BTG2, DHCR7, TGM1, GFRAl
GOTERM_ GO:0048856~anatomical
8 0,9986172 EGFR, BTG2, DHCR7, CH B, TGM1, TIRAP, GFRAl, HES6 100 BP ALL structure development
GOTERM_ GO:0009653~anatomical
3 0,9986286 EGFR, TGM1, GFRAl 100 BP_ALL structure morphogenesis
GOTERM_
GO:0048513~organ development 5 0,9992404 EGFR, DHCR7, CHKB, TGM1, TIRAP 100 BP ALL
GOTERM_ GO:0007275~multicellular EGFR, BTG2, HMGCR, DHCR7, CHKB, TGM1, TIRAP, GFRAl,
9 0,9994912 100 BP_ALL organismal development HES6
GOTERM_ GO:0032501~multicellular EGFR, HMGCR, CREM, CHKB, TIRAP, HES6, G6PC, CD36, BTG2,
14 0,9999987 100 BP_ALL organismal process DHCR7, TGM1, PDE4B, GFRAl, COMT1
GOTERM_ GO:0007166~cell surface receptor
3 1 EGFR, TIRAP, GFRAl 100 BP ALL linked signal transduction
Annotation Enrichment Score:
Cluster 19 3.323031420475828E,4
Gene
Category Term PValue Genes FDR
Count
ENPP5, HMGCR, CREM, CHKB, ATP11A, HES6, MBD1,
GOTERM_ GO:0006807~nitrogen compound
16 0,9922124 CYP4A10, LYVE1, G6PC, P4HA2, BTG2, CYP4A31, VNN1, 100 BP_ALL metabolic process
PABPC1, COMT1, FABP5
GOTERM_ GO:0019222~regulation of EGFR, HMGCR, KLK1B4, CREM, TIRAP, UBE2L6, PNPLA2, HES6,
13 0,9974859 100 BP ALL metabolic process MBD1, CYP4A10, G6PC, BTG2, DYNLL1, CYP4A31
GOTERM_ GO:0034641~cellular nitrogen ENPP5, HMGCR, CREM, CHKB, ATP11A, HES6, MBD1,
13 0,9989558 100 BP ALL compound metabolic process CYP4A10, G6PC, BTG2, CYP4A31, PABPC1, COMT1, FABP5
GOTERM_ GO:0031323~regulation of CYP4A10, EGFR, BTG , DYNLL1, KLK1B4, HMGCR, CREM,
11 0,9990961 100 BP ALL cellular metabolic process CYP4A31, TIRAP, PNPLA2, HES6, MBD1
GOTERM_ GO:0080090~regulation of CYP4A10, EGFR, BTG2, KLK1B4, CREM, CYP4A31, TIRAP,
10 0,9993803 100 BP ALL primary metabolic process UBE2L6, PNPLA2, HES6, MB01
GOTERM_
GO:0006350~transcription 5 0,9996423 CYP4A10, BTG2, CREM, CYP4A31, HES6, MBD1 100 BP ALL
GOTERM_ GO:0060255~regulation of CYP4A10, EGFR, G6PC, BTG2, CREM, CYP4A31, TIRAP, UBE2L6,
9 0,9998224 100 BP ALL macromolecule metabolic process HES6, MBD1
GO:0034645~cellular
GOTERM_
macromolecule biosynthetic 7 0,999911 CYP4A10, BTG2, CREM, CYP4A31, EIF1A, HES6, PIGP, MBD1 100 BP_ALL
process
GOTERM_ GO:0009059~macromolecule
7 0,9999158 CYP4A10, BTG2, CREM, CYP4A31, EIF1A, HES6, PIGP, MBD1 100 BP ALL biosynthetic process
GO:0006139~nucleobase,
GOTERM_ ENPP5, CYP4A10, BTG2, HMGCR, CREM, CYP4A31, ATP11A, nucleoside, nucleotide and 9 0,9999503 100 BP_ALL PABPC1, HES6, MBD1
nucleic acid metabolic process
GOTERM_ CYP4A10, BTG2, CREM, CYP4A31, EIF1A, PABPC1, HES6,
GO:0010467~gene expression 7 0,9999735 100 BP ALL MBD1
GO:0051171~regulation of
GOTERM_
nitrogen compound metabolic 6 0,9999763 CYP4A10, BTG2, DYNLL1, CREM, CYP4A31, HES6, MBD1 100 BP_ALL
process
GOTERM_ GO:0010468~regulation of gene
6 0,9999844 CYP4A10, G6PC, BTG2, CREM, CYP4A31, HES6, MBD1 100 BP_ALL expression
GOTERM_ GO:0045449~regulation of
5 0,9999871 CYP4A10, BTG2, CREM, CYP4A31, HES6, MBD1 100 BP ALL transcription
GOTERM_ GO:0031326~regulation of
6 0,9999882 CYP4A10, BTG2, DYNLL1, CREM, CYP4A31, HES6, MBD1 100 BP ALL cellular biosynthetic process
GOTERM_ GO:0009889~regulation of
6 0,999989 CYP4A10, BTG2, DYNLL1, CREM, CYP4A31, HES6, MBD1 100 BP ALL biosynthetic process
GO:0019219~regulation of
GOTERM_ nucleobase, nucleoside,
5 0,9999951 CYP4A10, BTG2, CREM, CYP4A31, HES6, MBD1 100 BP_ALL nucleotide and nucleic acid
metabolic process
GO:0010556~regulation of
GOTERM_
macromolecule biosynthetic 5 0,9999961 CYP4A10, BTG2, CREM, CYP4A31, HES6, MBD1 100 BP_ALL
process
Annotation Enrichment Score:
Cluster 20 9.391368293707048E-5
Gene
Category Term PValue Genes FDR
Count KLK1B4, HMGCR, CREM, TIRAP, PRDX4, APOA4, ARHGAP6,
TIAM2, DYNLLl, DHCR7, PDE4B, VNNl, TRAF3, GLRX, EGFR,
GOTERM_
GO:0065007~biological regulation 37 0,9996474 PDK4, LIFR, PIM1, UBE2L6, SPSB4, PNPLA2, TKT, HES6, 100 BP_ALL
MID1IP1, MBD1, CIDEC, PEX11A, CYP4A10, ORM1, G6PC, RAB30, CD36, BTG2, RAB17, CYP4A31, RDH16, COMT1
KLK1B4, HMGCR, CREM, PRDX4, TIRAP, APOA4, ARHGAP6, TIAM2, DYNLLl, DHCR7, PDE4B, VNNl, TRAF3, GLRX, EGFR,
GOTERM_ GO:0050789~regulation of
34 0,9997322 PDK4, LIFR, PIM1, UBE2L6, SPSB4, PNPLA2, TKT, HES6, 100 BP_ALL biological process
MID1IP1, MBD1, CIDEC, PEX11A, CYP4A10, ORM1, G6PC, RAB30, CD36, BTG2, RAB17, CYP4A31
KLK1B4, HMGCR, CREM, PRDX4, TIRAP, ARHGAP6, TIAM2,
GOTERM_ GO:0050794~regulation of DYNLLl, DHCR7, PDE4B, VNNl, TRAF3, GLRX, EGFR, PDK4,
29 0,9999717 100 BP_ALL cellular process PIM1, LIFR, SPSB4, PIMPLA2, HES6, MID1IP1, MBD1, CIDEC,
PEX11A, CYP4A10, CD36, RAB30, BTG2, RAB17, CYP4A31
Sequence and chromatin immunoprecipitation analyses (ChIP) provided conclusive evidence that TFEB binds to PGCla and PPARa promoters and directly regulates their expression during starvation (Fig. 4D). These data suggest that TFEB control on lipid metabolism is mediated, at least in part, by these two genes.
Previous studies demonstrated that TFEB, together with Target of Rapamycin Complex 1 (mTORCl), is involved in sensing lysosomal nutrient levels and signaling this information to the nucleus (5). Starvation inhibits mTORCl -mediated TFEB phosphorylation, which in turn promotes TFEB nuclear translocation and transcriptional activation of its target genes (5). Here the authors show that, once induced by starvation, TFEB turns on a transcriptional response that enhances FFA catabolism and ketogenesis. The authors propose that this mechanism is likely to have evolved as an adaptation to food deprivation. Importantly, the possibility of pharmacologically inducing TFEB activity (5) makes it an attractive therapeutic target for the modulation of lipid metabolism in obesity-related diseases. Moreover TFEB variants that are constitutively localized in the nucleus of a eukaryote cell, such as TFEB(S142A) and TFEB(S211A) mutant, have a therapeutic applicability in obesity-related diseases, as well.
References
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3. M. Sardiello et al, Science 325, 473 (2009).
4. C. Settembre et al, Science 332, 1429 (2011).
5. C. Settembre et al, EMBO J31, 1095 (2012).
6. F. Vetrini, P. Ng, Curr Pharm Des 17, 2488 (2011).
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8. C. Vaisse et al, Nat Genet 14, 95 (1996).
9. G. Dennis, Jr. et al, Genome Biol 4, P3 (2003).
10. W. Huang da, B. T. Sherman, R. A. Lempicki, Nat Protoc 4, 44 (2009)
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Claims

I . A vector comprising a TFEB coding sequence, or a functional or allelic variant or derivative or fragment thereof, under the control of a promoter able to efficiently express said TFEB coding sequence for use in the treatment of obesity and/or metabolic syndrome.
2. The vector according to claim 1 wherein the TFEB coding sequence is comprised in the sequence being essentially SEQ ID No. 1.
3. The vector according to any of previous claims being a viral vector.
4. The vector according to claim 3 selected from the group consisting of: adenoviral vectors, lentiviral vectors, retroviral vectors, adeno associated vectors (AAV) and naked plasmid DNA vectors.
5. The vector according to claim 4 selected from the group consisting of helper-dependent adenoviral vectors.
6. The vector according to any of the previous claims comprising a liver specific promoter and/or regulatory sequences.
7. The vector according to claim 6 wherein the liver specific promoter is phosphoenolpyruvate carboxykinase (PEPCK) promoter having essentially the sequence of SEQ ID No. 2.
8. The vector according to claim 6 or 7 wherein the liver regulative sequence is the liver specific enhancer Locus Control Region (LCR) from the apoE locus having essentially the sequence of SEQ ID No. 3.
9. The vector according to any of previous claims comprising a nucleotide sequence having essentially the sequence SEQ ID No. 4.
10. The vector according to any one of previous claim wherein said vector enhances lipid breakdown.
I I . An host cell transformed by the vector according to any of previous claims for use in the treatment of obesity and/or metabolic syndrome.
12. A viral particle containing the vector according to any of claim 1 to 10 for use in the treatment of obesity and/or metabolic syndrome.
13. A pharmaceutical composition comprising the vector according to any of previous claims 1- 10 or the host cell according to claim 1 1 or the viral particle according to claim 12 for use in the treatment of obesity and/or metabolic syndrome.
14. A method for the treatment of obesity and/or metabolic syndrome of a subject in need thereof, said method comprising administering an effective amount of the pharmaceutical composition according to claim 13.
15. A TFEB coding sequence, protein or a functional or allelic variant thereof or a TFEB protein, synthetic or biotechno logical functional derivative thereof, peptide fragments thereof, chimeric molecules comprising the TFEB protein, synthetic or biotechnological functional derivative thereof for use in the treatment of an obesity and/or metabolic syndrome.
16. A method of treatment of obesity and/or metabolic syndrome comprising administering an effective amount of a TFEB coding sequence, protein or a functional or allelic variant thereof or a TFEB protein, synthetic or biotechnological functional derivative thereof, peptide fragments thereof, chimeric molecules comprising the TFEB protein, synthetic or biotechnological functional derivative thereof to a patient in need thereof.
17. A method for enhancing lipid breakdown comprising the administration of TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof.
18. The method according to claim 17 wherein the administration of TFEB is made by gene therapy or by the administration of a pharmaceutical composition comprising TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof.
19. The method according to any of claims 17-18 wherein the TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof enhances free fatty acid (FFA) catabolism and ketogenesis.
20. The method according to any of claims 17-19 wherein TFEB coding sequence, protein or a functional or allelic variant or derivative or fragment thereof regulates genes expression by upregulating genes related to lipid breakdown and/or downregulating genes related to lipid biosynthesis and/or in inflammatory response.
21. The method according to claim 20 wherein TFEB coding sequence, protein or a functional or allelic variant thereof acts through the binding to said genes promoters.
22. The method according to claim 20 or 21 wherein the upregulated gene is PGCla and/or PPARa.
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