Networks offer an intuitive visual representation of complex systems. Important network character... more Networks offer an intuitive visual representation of complex systems. Important network characteristics can often be recognized by eye and, in turn, patterns that stand out visually often have a meaningful interpretation. In conventional network layout algorithms, however, the precise determinants of a node’s position within a layout are difficult to decipher and to control. Here we propose an approach for directly encoding arbitrary structural or functional network characteristics into node positions. We introduce a series of two- and three-dimensional layouts, benchmark their efficiency for model networks, and demonstrate their power for elucidating structure-to-function relationships in large-scale biological networks.
# High-content imaging chemical screen in U-2-OS<br><br>This dataset is described in ... more # High-content imaging chemical screen in U-2-OS<br><br>This dataset is described in the manuscript untitled "BioProfiling.jl: Profiling biological perturbations with high-content imaging in single cells and heterogeneous populations" by Vulliard _et al_ (DOI: [10.1101/2021.06.18.448961](https://doi.org/10.1101/2021.06.18.448961).<br>The following files are made available:<br><br>* `README.md`: description of the dataset.<br>* `750CellsPerWell.zip`: raw fluorescent images (TIFF) for a 384-well drug plate seeded with 750 cells per well.<br>* `1500CellsPerWell.zip`: raw fluorescent images (TIFF) for a 384-well drug plate seeded with 1500 cells per well.<br>* `Batch_data_u2os_drug.cpproj`: CellProfiler 3.1.8 pipeline used to analyse the images.<br>* `data.zip`: morphological measurements from CellProfiler per cell for each plate and plate layout. Necessary input to reproduce our [example analyses](https://github.com/menchelab/BioProfilingNotebooks).<br><br>The preparation of the drug plates is described more precisely in the manuscript.
Genes and Pathways relating COPD and DG8. The figure shows the association between Reactome (a) a... more Genes and Pathways relating COPD and DG8. The figure shows the association between Reactome (a) and Biocarta (b) pathways for most-associated ICD9 codes included in DG8. A dark (light) blue square denotes that the association between disease and pathway or gene was computed as significant when using either mapping1_DG or mapping2_DG (only mapping1_DG). The description of the ICD9 codes is provided in panel (c). Additional file 9: Figure S8 extends the information provided in Fig. 5 and follows the same color-code and selection criteria. (PDF 1550 kb)
Text-mining analysis by PolySearch. set1 = ("aging", "age"), set2 = ("sm... more Text-mining analysis by PolySearch. set1 = ("aging", "age"), set2 = ("smoking","smoke"), set3 = ("training","train","healthy life style"); the results of the queries are shown in Additional file 14: Tables S4, S5 and S6 respectively. (ZIP 97 kb)
Rare genetic diseases are typically caused by a single gene defect. Despite this clear causal rel... more Rare genetic diseases are typically caused by a single gene defect. Despite this clear causal relationship between genotype and phenotype, identifying the pathobiological mechanisms at various levels of biological organization remains a practical and conceptual challenge. Here, we introduce a network approach for evaluating the impact of rare gene defects across biological scales. We construct a multiplex network consisting of over 20 million gene relationships that are organized into 46 network layers spanning six major biological scales between genotype and phenotype. A comprehensive analysis of 3,771 rare diseases reveals distinct phenotypic modules within individual layers. These modules can be exploited to mechanistically dissect the impact of gene defects and accurately predict rare disease gene candidates. Our results show that the disease module formalism can be applied to rare diseases and generalized beyond physical interaction networks. These findings open up new venues t...
MotivationHigh-content imaging screens provide a cost-effective and scalable way to assess cell s... more MotivationHigh-content imaging screens provide a cost-effective and scalable way to assess cell states across diverse experimental conditions. The analysis of the acquired microscopy images involves assembling and curating morphological measurements of individual cells into morphological profiles suitable for testing biological hypotheses. Despite being a critical step, there is currently no standard approach to morphological profiling and no solution is available for the high-performance Julia programming language.ResultsHere, we introduce BioProfiling.jl, an efficient end-to-end solution for compiling and filtering informative morphological profiles in Julia. The package contains all the necessary data structures to curate morphological measurements and helper functions to transform, normalize and visualize profiles. Robust statistical distances and permutation tests enable quantification of the significance of the observed changes despite the high fraction of outliers inherent to...
Abstract From protein interactions to signal transduction, from metabolism to the nervous system:... more Abstract From protein interactions to signal transduction, from metabolism to the nervous system: Virtually all processes in health and disease rely on the careful orchestration of a large number of diverse individual components ranging from molecules to cells and entire organs. Networks provide a powerful framework for describing and understanding these complex systems in a wholistic fashion. They offer a unique combination of a highly intuitive, qualitative description, and a plethora of analytical, quantitative tools. Here we provide a brief introduction to the emerging field of network medicine. After an overview of the core concepts for connecting network characteristics to biological functions, we review commonly used networks, ranging from the molecular interaction networks that form the basis of all biological processes in the cell to the global transportation networks that govern the spread of global epidemics. Lastly, we highlight current conceptual and practical challenges.
Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue... more Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. ...
Invited for this month′s cover is the group of Miriam Unterlass at the Technische Universität Wie... more Invited for this month′s cover is the group of Miriam Unterlass at the Technische Universität Wien and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. The image illustrates the synthesis of quinoxalines in “hot water” and the large‐scale computational comparison of all existing syntheses of these quinoxalines. The Full Paper itself is available at 10.1002/cssc.202100433.
Drug combinations provide effective treatments for diverse diseases, but also represent a major c... more Drug combinations provide effective treatments for diverse diseases, but also represent a major cause of adverse reactions. Currently there is no systematic understanding of how the complex cellular perturbations induced by different drugs influence each other. Here, we introduce a mathematical framework for classifying any interaction between perturbations with high-dimensional effects into 12 interaction types. We apply our framework to a large-scale imaging screen of cell morphology changes induced by diverse drugs and their combination, resulting in a perturbome network of 242 drugs and 1832 interactions. Our analysis of the chemical and biological features of the drugs reveals distinct molecular fingerprints for each interaction type. We find a direct link between drug similarities on the cell morphology level and the distance of their respective protein targets within the cellular interactome of molecular interactions. The interactome distance is also predictive for different ...
Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided ... more Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided into entities with distinct clinical features. Somatic mutations in JAK2, CALR, and MPL have been described as drivers of the disease, together with a variable landscape of nondriver mutations. Despite detailed knowledge of disease mechanisms, targeted therapies effective enough to eliminate MPN cells are still missing. In this study of 113 MPN patients, we aimed to comprehensively characterize the mutational landscape of the granulocyte transcriptome using RNA sequencing data and subsequently examine the applicability of immunotherapeutic strategies for MPN patients. Following implementation of customized workflows and data filtering, we identified a total of 13 (12/13 novel) gene fusions, 231 nonsynonymous single nucleotide variants, and 21 insertions and deletions in 106 of 113 patients. We found a high frequency of SF3B1-mutated primary myelofibrosis patients (14%) with distinct 3′ s...
Background: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause... more Background: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell–activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus, and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. Methods: To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe −/− and Ldlr −/− mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which B...
Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from ... more Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive. We investigated CCR2 mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis. We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non...
Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fan... more Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities, and increased cancer risk that is caused by defective repair of DNA interstrand crosslinks (ICLs). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies by performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2). Thus, as compared to FA-defective cells alone, FA-deficient cells additionally lacking USP48 are less sensitive to genotoxic stress induced by ICL agents and display enhanced, BRCA1-dependent, clearance of DNA damage. Consequently, USP48 inactivation reduces chromosomal instability of FA-defective cells. Our results highlight a role for USP48 in controlling DNA repair and suggest it as a potential target that could be therapeutically exploited for FA.
Probing the dynamic control features of biological networks represents a new frontier in capturin... more Probing the dynamic control features of biological networks represents a new frontier in capturing the dysregulated pathways in complex diseases. Here, using patient samples obtained from a pancreatic islet transplantation program, we constructed a tissue-specific gene regulatory network and used the control centrality (Cc) concept to identify the high control centrality (HiCc) pathways, which might serve as key pathobiological pathways for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS -values in the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study. We identified variants regulating gene expression (expression quantitative loci, eQTL) of HiCc pathway genes in islet samples. These eQTL genes showed higher levels of differential expression compared to non-eQTL genes in low, medium, and high glucose concentrations in rat islets. Among genes with highly significant eQTL evidence, NFATC4 belonged to four HiCc pathways....
Maintenance of genome integrity via repair of DNA damage is a key biological process required to ... more Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, including Fanconi anemia (FA). We generated loss-of-function human haploid cells for FA complementation group C (FANCC), a gene encoding a component of the FA core complex, and used genome-wide CRISPR libraries as well as insertional mutagenesis to identify synthetic viable (genetic suppressor) interactions for FA. Here we show that loss of the BLM helicase complex suppresses FANCC phenotypes and we confirm this interaction in cells deficient for FA complementation group I and D2 (FANCI and FANCD2) that function as part of the FA I-D2 complex, indicating that this interaction is not limited to the FA core complex, hence demonstrating that systematic genome-wide screening approaches can be used to reveal genetic viable interactions for DNA repair defects.
Gene expression data are routinely used to identify genes that on average exhibit different expre... more Gene expression data are routinely used to identify genes that on average exhibit different expression levels between a case and a control group. Yet, very few of such differentially expressed genes are detectably perturbed in individual patients. Here, we develop a framework to construct personalized perturbation profiles for individual subjects, identifying the set of genes that are significantly perturbed in each individual. This allows us to characterize the heterogeneity of the molecular manifestations of complex diseases by quantifying the expression-level similarities and differences among patients with the same phenotype. We show that despite the high heterogeneity of the individual perturbation profiles, patients with asthma, Parkinson and Huntington's disease share a broadpool of sporadically disease-associated genes, and that individuals with statistically significant overlap with this pool have a 80-100% chance of being diagnosed with the disease. The developed frame...
Networks offer an intuitive visual representation of complex systems. Important network character... more Networks offer an intuitive visual representation of complex systems. Important network characteristics can often be recognized by eye and, in turn, patterns that stand out visually often have a meaningful interpretation. In conventional network layout algorithms, however, the precise determinants of a node’s position within a layout are difficult to decipher and to control. Here we propose an approach for directly encoding arbitrary structural or functional network characteristics into node positions. We introduce a series of two- and three-dimensional layouts, benchmark their efficiency for model networks, and demonstrate their power for elucidating structure-to-function relationships in large-scale biological networks.
# High-content imaging chemical screen in U-2-OS<br><br>This dataset is described in ... more # High-content imaging chemical screen in U-2-OS<br><br>This dataset is described in the manuscript untitled "BioProfiling.jl: Profiling biological perturbations with high-content imaging in single cells and heterogeneous populations" by Vulliard _et al_ (DOI: [10.1101/2021.06.18.448961](https://doi.org/10.1101/2021.06.18.448961).<br>The following files are made available:<br><br>* `README.md`: description of the dataset.<br>* `750CellsPerWell.zip`: raw fluorescent images (TIFF) for a 384-well drug plate seeded with 750 cells per well.<br>* `1500CellsPerWell.zip`: raw fluorescent images (TIFF) for a 384-well drug plate seeded with 1500 cells per well.<br>* `Batch_data_u2os_drug.cpproj`: CellProfiler 3.1.8 pipeline used to analyse the images.<br>* `data.zip`: morphological measurements from CellProfiler per cell for each plate and plate layout. Necessary input to reproduce our [example analyses](https://github.com/menchelab/BioProfilingNotebooks).<br><br>The preparation of the drug plates is described more precisely in the manuscript.
Genes and Pathways relating COPD and DG8. The figure shows the association between Reactome (a) a... more Genes and Pathways relating COPD and DG8. The figure shows the association between Reactome (a) and Biocarta (b) pathways for most-associated ICD9 codes included in DG8. A dark (light) blue square denotes that the association between disease and pathway or gene was computed as significant when using either mapping1_DG or mapping2_DG (only mapping1_DG). The description of the ICD9 codes is provided in panel (c). Additional file 9: Figure S8 extends the information provided in Fig. 5 and follows the same color-code and selection criteria. (PDF 1550 kb)
Text-mining analysis by PolySearch. set1 = ("aging", "age"), set2 = ("sm... more Text-mining analysis by PolySearch. set1 = ("aging", "age"), set2 = ("smoking","smoke"), set3 = ("training","train","healthy life style"); the results of the queries are shown in Additional file 14: Tables S4, S5 and S6 respectively. (ZIP 97 kb)
Rare genetic diseases are typically caused by a single gene defect. Despite this clear causal rel... more Rare genetic diseases are typically caused by a single gene defect. Despite this clear causal relationship between genotype and phenotype, identifying the pathobiological mechanisms at various levels of biological organization remains a practical and conceptual challenge. Here, we introduce a network approach for evaluating the impact of rare gene defects across biological scales. We construct a multiplex network consisting of over 20 million gene relationships that are organized into 46 network layers spanning six major biological scales between genotype and phenotype. A comprehensive analysis of 3,771 rare diseases reveals distinct phenotypic modules within individual layers. These modules can be exploited to mechanistically dissect the impact of gene defects and accurately predict rare disease gene candidates. Our results show that the disease module formalism can be applied to rare diseases and generalized beyond physical interaction networks. These findings open up new venues t...
MotivationHigh-content imaging screens provide a cost-effective and scalable way to assess cell s... more MotivationHigh-content imaging screens provide a cost-effective and scalable way to assess cell states across diverse experimental conditions. The analysis of the acquired microscopy images involves assembling and curating morphological measurements of individual cells into morphological profiles suitable for testing biological hypotheses. Despite being a critical step, there is currently no standard approach to morphological profiling and no solution is available for the high-performance Julia programming language.ResultsHere, we introduce BioProfiling.jl, an efficient end-to-end solution for compiling and filtering informative morphological profiles in Julia. The package contains all the necessary data structures to curate morphological measurements and helper functions to transform, normalize and visualize profiles. Robust statistical distances and permutation tests enable quantification of the significance of the observed changes despite the high fraction of outliers inherent to...
Abstract From protein interactions to signal transduction, from metabolism to the nervous system:... more Abstract From protein interactions to signal transduction, from metabolism to the nervous system: Virtually all processes in health and disease rely on the careful orchestration of a large number of diverse individual components ranging from molecules to cells and entire organs. Networks provide a powerful framework for describing and understanding these complex systems in a wholistic fashion. They offer a unique combination of a highly intuitive, qualitative description, and a plethora of analytical, quantitative tools. Here we provide a brief introduction to the emerging field of network medicine. After an overview of the core concepts for connecting network characteristics to biological functions, we review commonly used networks, ranging from the molecular interaction networks that form the basis of all biological processes in the cell to the global transportation networks that govern the spread of global epidemics. Lastly, we highlight current conceptual and practical challenges.
Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue... more Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. ...
Invited for this month′s cover is the group of Miriam Unterlass at the Technische Universität Wie... more Invited for this month′s cover is the group of Miriam Unterlass at the Technische Universität Wien and the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. The image illustrates the synthesis of quinoxalines in “hot water” and the large‐scale computational comparison of all existing syntheses of these quinoxalines. The Full Paper itself is available at 10.1002/cssc.202100433.
Drug combinations provide effective treatments for diverse diseases, but also represent a major c... more Drug combinations provide effective treatments for diverse diseases, but also represent a major cause of adverse reactions. Currently there is no systematic understanding of how the complex cellular perturbations induced by different drugs influence each other. Here, we introduce a mathematical framework for classifying any interaction between perturbations with high-dimensional effects into 12 interaction types. We apply our framework to a large-scale imaging screen of cell morphology changes induced by diverse drugs and their combination, resulting in a perturbome network of 242 drugs and 1832 interactions. Our analysis of the chemical and biological features of the drugs reveals distinct molecular fingerprints for each interaction type. We find a direct link between drug similarities on the cell morphology level and the distance of their respective protein targets within the cellular interactome of molecular interactions. The interactome distance is also predictive for different ...
Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided ... more Ph-negative myeloproliferative neoplasms (MPNs) are hematological cancers that can be subdivided into entities with distinct clinical features. Somatic mutations in JAK2, CALR, and MPL have been described as drivers of the disease, together with a variable landscape of nondriver mutations. Despite detailed knowledge of disease mechanisms, targeted therapies effective enough to eliminate MPN cells are still missing. In this study of 113 MPN patients, we aimed to comprehensively characterize the mutational landscape of the granulocyte transcriptome using RNA sequencing data and subsequently examine the applicability of immunotherapeutic strategies for MPN patients. Following implementation of customized workflows and data filtering, we identified a total of 13 (12/13 novel) gene fusions, 231 nonsynonymous single nucleotide variants, and 21 insertions and deletions in 106 of 113 patients. We found a high frequency of SF3B1-mutated primary myelofibrosis patients (14%) with distinct 3′ s...
Background: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause... more Background: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell–activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus, and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. Methods: To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe −/− and Ldlr −/− mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which B...
Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from ... more Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive. We investigated CCR2 mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis. We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non...
Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fan... more Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities, and increased cancer risk that is caused by defective repair of DNA interstrand crosslinks (ICLs). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies by performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2). Thus, as compared to FA-defective cells alone, FA-deficient cells additionally lacking USP48 are less sensitive to genotoxic stress induced by ICL agents and display enhanced, BRCA1-dependent, clearance of DNA damage. Consequently, USP48 inactivation reduces chromosomal instability of FA-defective cells. Our results highlight a role for USP48 in controlling DNA repair and suggest it as a potential target that could be therapeutically exploited for FA.
Probing the dynamic control features of biological networks represents a new frontier in capturin... more Probing the dynamic control features of biological networks represents a new frontier in capturing the dysregulated pathways in complex diseases. Here, using patient samples obtained from a pancreatic islet transplantation program, we constructed a tissue-specific gene regulatory network and used the control centrality (Cc) concept to identify the high control centrality (HiCc) pathways, which might serve as key pathobiological pathways for Type 2 Diabetes (T2D). We found that HiCc pathway genes were significantly enriched with modest GWAS -values in the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study. We identified variants regulating gene expression (expression quantitative loci, eQTL) of HiCc pathway genes in islet samples. These eQTL genes showed higher levels of differential expression compared to non-eQTL genes in low, medium, and high glucose concentrations in rat islets. Among genes with highly significant eQTL evidence, NFATC4 belonged to four HiCc pathways....
Maintenance of genome integrity via repair of DNA damage is a key biological process required to ... more Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, including Fanconi anemia (FA). We generated loss-of-function human haploid cells for FA complementation group C (FANCC), a gene encoding a component of the FA core complex, and used genome-wide CRISPR libraries as well as insertional mutagenesis to identify synthetic viable (genetic suppressor) interactions for FA. Here we show that loss of the BLM helicase complex suppresses FANCC phenotypes and we confirm this interaction in cells deficient for FA complementation group I and D2 (FANCI and FANCD2) that function as part of the FA I-D2 complex, indicating that this interaction is not limited to the FA core complex, hence demonstrating that systematic genome-wide screening approaches can be used to reveal genetic viable interactions for DNA repair defects.
Gene expression data are routinely used to identify genes that on average exhibit different expre... more Gene expression data are routinely used to identify genes that on average exhibit different expression levels between a case and a control group. Yet, very few of such differentially expressed genes are detectably perturbed in individual patients. Here, we develop a framework to construct personalized perturbation profiles for individual subjects, identifying the set of genes that are significantly perturbed in each individual. This allows us to characterize the heterogeneity of the molecular manifestations of complex diseases by quantifying the expression-level similarities and differences among patients with the same phenotype. We show that despite the high heterogeneity of the individual perturbation profiles, patients with asthma, Parkinson and Huntington's disease share a broadpool of sporadically disease-associated genes, and that individuals with statistically significant overlap with this pool have a 80-100% chance of being diagnosed with the disease. The developed frame...
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