Epigenetic modifications are known to regulate cell phenotype during cancer progression, includin... more Epigenetic modifications are known to regulate cell phenotype during cancer progression, including breast cancer. Unlike genetic alterations, changes in the epigenome are reversible, thus potentially reversed by epi-drugs. Breast cancer, the most common cause of cancer death worldwide in women, encompasses multiple histopathological and molecular subtypes. Several lines of evidence demonstrated distortion of the epigenetic landscape in breast cancer. Interestingly, mammary cells isolated from breast cancer patients and cultured ex vivo maintained the tumorigenic phenotype and exhibited aberrant epigenetic modifications. Recent studies indicated that the therapeutic efficiency for breast cancer regimens has increased over time, resulting in reduced mortality. Future medical treatment for breast cancer patients, however, will likely depend upon a better understanding of epigenetic modifications. The present review aims to outline different epigenetic mechanisms including DNA methylati...
Small cell lung cancer (SCLC) is an extremely aggressive lung cancer type with a patient median s... more Small cell lung cancer (SCLC) is an extremely aggressive lung cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC has remained elusive. We analyzed RNA-sequencing data, human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines to demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which might be used for stratification of SCLC patients, prognosis prediction of LC patients and development of patient-tailored therapies. We also found by pr...
Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to ... more Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could b...
Environmental factors, including pollutants and lifestyle, constitute a significant role in sever... more Environmental factors, including pollutants and lifestyle, constitute a significant role in severe, chronic pathologies with an essential societal, economic burden. The measurement of all environmental exposures and assessing their correlation with effects on individual health is defined as the exposome, which interacts with our unique characteristics such as genetics, physiology, and epigenetics. Epigenetics investigates modifications in the expression of genes that do not depend on the underlying DNA sequence. Some studies have confirmed that environmental factors may promote disease in individuals or subsequent progeny through epigenetic alterations. Variations in the epigenetic machinery cause a spectrum of different disorders since these mechanisms are more sensitive to the environment than the genome, due to the inherent reversible nature of the epigenetic landscape. Several epigenetic mechanisms, including modifications in DNA (e.g., methylation), histones, and noncoding RNAs...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is worldwide the main cause of t... more The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is worldwide the main cause of the COVID-19 pandemic. After infection of human pulmonary cells, intracellular viral replication take place in different cellular compartments resulting in the destruction of the host cells and causing severe respiratory diseases. Although cellular trafficking of SARS-CoV-2 have been explored, little is known about the role of the cytoskeleton during viral replication in pulmonary cells. Here we show that SARS-CoV-2 infection induces dramatic changes of F-actin nanostructures overtime. Ring-like actin nanostructures are surrounding viral intracellular organelles, suggesting a functional interplay between F-actin and viral M clusters during particle assembly. Filopodia-like structures loaded with viruses to neighbour cells suggest these structures as mechanism for cell-to-cell virus transmission. Strikingly, gene expression profile analysis and PKN inhibitor treatments of infected pulmonar...
Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts ... more Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2, proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d. Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lun...
Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling... more Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal recessive disease known as immunodeficiency-centromeric instability-facial anomaly (ICF) syndrome. Interestingly, LSH participates in various aspects of epigenetic regulation, including nucleosome remodelling, DNA methylation, histone modifications and heterochromatin formation. Further, LSH plays a crucial role during DNA-damage repair, specifically during double-strand break (DSB) repair, since murine LSH was shown to be essential for non-homologous end joining (NHEJ) and homologous recombination (HR). Accordingly, overexpression of LSH drives tumorigenesis and malignancy. On the other hand, LSH homologs stabilise the genome. Thus, LSH might be implemented as a biomarker for various cancer types and potential target molecule to develop therapeutic strategies against them. In this review, we focus on the role of LSH in orchestrating chromatin rearrangements, such as DNA methylation and histone modifications, as well as in DNA-damage repair. Changes in chromatin structure may facilitate gene expression signatures that cause malignant transformation. We summarise recent findings of LSH in cancers and raise critical open questions for further studies.
Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. On the other hand, idio... more Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. On the other hand, idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease showing a prevalence of 20 new cases per 100,000 persons per year. Despite differences in cellular origin and pathological phenotypes, LC and IPF are lung diseases that share common features, including hyperproliferation of specific cell types in the lung, involvement of epithelial-mesenchymal transition (EMT) and enhanced activity of signaling pathways, such as tissue growth factor (TGFB), epidermal growth factor (EGF), fibroblast growth factor (FGF), wingless secreted glycoprotein (WNT) signaling, among others. EMT is a process during which epithelial cells lose their cell polarity and cell-cell adhesion, and acquire migratory and invasive properties to become mesenchymal cells. EMT involves numerous morphological hallmarks of hyperproliferative diseases, like cell plasticity, resistance to apoptosis, dedifferentiation and proliferation, thereby playing a central role during organ fibrosis and cancer progression. EMT was considered as an "all-or-none" process. In contrast to these outdated dichotomist interpretations, recent reports suggest that EMT occurs gradually involving different epithelial cell intermediate states with mesenchyme-like characteristics. These cell intermediate states of EMT differ from each other in their cell plasticity, invasiveness and metastatic potential, which in turn are induced by signals from their microenvironment. EMT is regulated by several transcription factors (TFs), which are members of prominent families of master regulators of transcription. In addition, there is increasing evidence for the important contribution of noncoding RNAs (ncRNAs) to EMT. In our review we highlight articles dissecting the function of different ncRNAs subtypes and nuclear architecture in cell intermediate states of EMT, as well as their involvement in LC and IPF.
SUMMARYIn addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, ... more SUMMARYIn addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support that chromatin opening during tran...
In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractil... more In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractile-myofibroblasts, which pull the wound edges together ensuring proper tissue repair. Uncontrolled expansion of the myofibroblast population may, however, lead to excessive tissue scarring and finally to organ dysfunction. Here, we demonstrate that the loss of low-density lipoprotein receptor-related protein (LRP) 1 overactivates the JNK1/2-c-Jun-Fra-2 signaling pathway leading to the induction of α-SMA and periostin expression in human lung fibroblasts (hLF). These changes are accompanied by increased contractility of the cells and the integrin- and protease-dependent release of active transforming growth factor (TGF)-β1 from the extracellular matrix (ECM) stores. Liberation of active TGF-β1 from the ECM further enhances α-SMA and periostin expression thus accelerating the phenotypic switch of hLF. Global gene expression profiling of LRP1-depleted hLF revealed that the loss of LRP1 affects cytoskeleton reorganization, cell-ECM contacts, and ECM production. In line with these findings, fibrotic changes in the skin and lung of Fra-2 transgenic mice were associated with LRP1 depletion and c-Jun overexpression. Altogether, our results suggest that dysregulation of LRP1 expression in fibroblasts in healing tissue may lead to the unrestrained expansion of contractile myofibroblasts and thereby to fibrosis development. Further studies identifying molecules, which regulate LRP1 expression, may provide new therapeutic options for largely untreatable human fibrotic diseases.
Non-coding RNAs (ncRNAs) are important regulators of different biological processes in the nucleu... more Non-coding RNAs (ncRNAs) are important regulators of different biological processes in the nucleus of the cell as part of the machinery controlling the chromatin structure at specific loci. However, the full extent of the function of ncRNAs in the nucleus has remained elusive, since the involvement of nuclear microRNAs (miRNAs) has not been investigated. Here we deciphered the function of a specific miRNA during transcriptional regulation. We show that the mature miRNA directly binds to nuclear ncRNAs and the RNA exosome complex to induce heterochromatin through histone methyl transferases, SUV39H1 and EZH2, thereby silencing transcription. The mechanism of miRNA/exosome-mediated transcriptional silencing is biologically relevant within the context of transforming growth factor (TGFB1) signaling. Furthermore, we confirmed the mechanism of transcriptional regulation presented here using primary cells from control donors and patients with idiopathic pulmonary fibrosis (IPF), opening new possibilities for the development of novel therapeutic approaches IPF.
Accumulation of mutations causing aberrant changes in the genome promotes cancer. However, mutati... more Accumulation of mutations causing aberrant changes in the genome promotes cancer. However, mutations do not occur in every cancer subtype, suggesting additional events that trigger cancer. Chromatin rearrangements initiated by pioneer factors and architectural proteins are key events occurring before cancer-related genes are expressed. Both protein groups are also master regulators of important processes during embryogenesis. Several publications demonstrated that embryonic gene expression signatures are reactivated during cancer. This review article highlights current knowledge on pioneer factors and architectural proteins mediating chromatin rearrangements, which are the backbone of embryonic expression signatures promoting malignant transformation. Understanding chromatin rearrangements inducing embryonic expression signatures in adult cells might be the key to novel therapeutic approaches against cancers subtypes that arise without genomic mutations.
The eukaryotic cell nucleus consists of functionally specialized subcompartments. These nuclear s... more The eukaryotic cell nucleus consists of functionally specialized subcompartments. These nuclear sub‐compartments are biomolecular aggregates built of proteins, transcripts, and specific genome loci. The structure and function of each nuclear subcompartment are defined by the composition and dynamic interaction between these 3 components. The spatio‐temporal localization of biochemical reactions into membraneless nuclear subcompartments can be achieved through liquid‐liquid phase separation. Based on this organizing principle, nuclear sub‐compartments are droplet‐like structures that adopt spherical shapes, flow, and fuse like liquids or gels. In the present review, we bring into the spotlight seminal works elucidating the functional interactions between scaffold proteins, noncoding RNAs, and genomic loci, thereby inducing liquid‐liquid phase separation as an organizing principle for 3‐dimensional nuclear architecture. We also discuss the implications in different cancer types as well as the potential use of this knowledge to develop novel therapeutic strategies against cancer.—Rubio, K., Dobersch, S., Barreto, G. Functional interactions between scaffold proteins, noncoding RNAs, and genome loci induce liquid‐liquid phase separation as organizing principle for 3‐dimensional nuclear architecture: implications in cancer. FASEB J. 33, 5814–5822 (2019). www.fasebj.org
Epigenetic modifications are known to regulate cell phenotype during cancer progression, includin... more Epigenetic modifications are known to regulate cell phenotype during cancer progression, including breast cancer. Unlike genetic alterations, changes in the epigenome are reversible, thus potentially reversed by epi-drugs. Breast cancer, the most common cause of cancer death worldwide in women, encompasses multiple histopathological and molecular subtypes. Several lines of evidence demonstrated distortion of the epigenetic landscape in breast cancer. Interestingly, mammary cells isolated from breast cancer patients and cultured ex vivo maintained the tumorigenic phenotype and exhibited aberrant epigenetic modifications. Recent studies indicated that the therapeutic efficiency for breast cancer regimens has increased over time, resulting in reduced mortality. Future medical treatment for breast cancer patients, however, will likely depend upon a better understanding of epigenetic modifications. The present review aims to outline different epigenetic mechanisms including DNA methylati...
Small cell lung cancer (SCLC) is an extremely aggressive lung cancer type with a patient median s... more Small cell lung cancer (SCLC) is an extremely aggressive lung cancer type with a patient median survival of 6-12 months. Epidermal growth factor (EGF) signaling plays an important role in triggering SCLC. In addition, growth factor-dependent signals and alpha-, beta-integrin (ITGA, ITGB) heterodimer receptors functionally cooperate and integrate their signaling pathways. However, the precise role of integrins in EGF receptor (EGFR) activation in SCLC has remained elusive. We analyzed RNA-sequencing data, human precision-cut lung slices (hPCLS), retrospectively collected human lung tissue samples and cell lines to demonstrate that non-canonical ITGB2 signaling activates EGFR and RAS/MAPK/ERK signaling in SCLC. Further, we identified a novel SCLC gene expression signature consisting of 93 transcripts that were induced by ITGB2, which might be used for stratification of SCLC patients, prognosis prediction of LC patients and development of patient-tailored therapies. We also found by pr...
Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to ... more Proteoglycans are complex macromolecules formed of glycosaminoglycan chains covalently linked to core proteins through a linker tetrasaccharide common to heparan sulfate proteoglycans (HSPG) and chondroitin sulfate proteoglycans (CSPG). Biosynthesis of a single proteoglycan requires the expression of dozens of genes, which together create the large structural and functional diversity reflected by the numerous diseases or syndromes associated to their genetic variability. Among proteoglycans, HSPG are the most structurally and functionally complex. To decrease this complexity, we retrieved and linked information on pathogenic variants, polymorphism, expression, and literature databases for 50 genes involved in the biosynthesis of HSPG core proteins, heparan sulfate (HS) chains, and their linker tetrasaccharide. This resulted in a new gene organization and biosynthetic pathway representation in which the phenotypic continuum of disorders as linkeropathies and other pathologies could b...
Environmental factors, including pollutants and lifestyle, constitute a significant role in sever... more Environmental factors, including pollutants and lifestyle, constitute a significant role in severe, chronic pathologies with an essential societal, economic burden. The measurement of all environmental exposures and assessing their correlation with effects on individual health is defined as the exposome, which interacts with our unique characteristics such as genetics, physiology, and epigenetics. Epigenetics investigates modifications in the expression of genes that do not depend on the underlying DNA sequence. Some studies have confirmed that environmental factors may promote disease in individuals or subsequent progeny through epigenetic alterations. Variations in the epigenetic machinery cause a spectrum of different disorders since these mechanisms are more sensitive to the environment than the genome, due to the inherent reversible nature of the epigenetic landscape. Several epigenetic mechanisms, including modifications in DNA (e.g., methylation), histones, and noncoding RNAs...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is worldwide the main cause of t... more The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is worldwide the main cause of the COVID-19 pandemic. After infection of human pulmonary cells, intracellular viral replication take place in different cellular compartments resulting in the destruction of the host cells and causing severe respiratory diseases. Although cellular trafficking of SARS-CoV-2 have been explored, little is known about the role of the cytoskeleton during viral replication in pulmonary cells. Here we show that SARS-CoV-2 infection induces dramatic changes of F-actin nanostructures overtime. Ring-like actin nanostructures are surrounding viral intracellular organelles, suggesting a functional interplay between F-actin and viral M clusters during particle assembly. Filopodia-like structures loaded with viruses to neighbour cells suggest these structures as mechanism for cell-to-cell virus transmission. Strikingly, gene expression profile analysis and PKN inhibitor treatments of infected pulmonar...
Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts ... more Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2, proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d. Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lun...
Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling... more Lymphoid-specific helicase (LSH) is a member of the SNF2 helicase family of chromatin-remodelling proteins. Dysfunctions or mutations in LSH causes an autosomal recessive disease known as immunodeficiency-centromeric instability-facial anomaly (ICF) syndrome. Interestingly, LSH participates in various aspects of epigenetic regulation, including nucleosome remodelling, DNA methylation, histone modifications and heterochromatin formation. Further, LSH plays a crucial role during DNA-damage repair, specifically during double-strand break (DSB) repair, since murine LSH was shown to be essential for non-homologous end joining (NHEJ) and homologous recombination (HR). Accordingly, overexpression of LSH drives tumorigenesis and malignancy. On the other hand, LSH homologs stabilise the genome. Thus, LSH might be implemented as a biomarker for various cancer types and potential target molecule to develop therapeutic strategies against them. In this review, we focus on the role of LSH in orchestrating chromatin rearrangements, such as DNA methylation and histone modifications, as well as in DNA-damage repair. Changes in chromatin structure may facilitate gene expression signatures that cause malignant transformation. We summarise recent findings of LSH in cancers and raise critical open questions for further studies.
Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. On the other hand, idio... more Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. On the other hand, idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease showing a prevalence of 20 new cases per 100,000 persons per year. Despite differences in cellular origin and pathological phenotypes, LC and IPF are lung diseases that share common features, including hyperproliferation of specific cell types in the lung, involvement of epithelial-mesenchymal transition (EMT) and enhanced activity of signaling pathways, such as tissue growth factor (TGFB), epidermal growth factor (EGF), fibroblast growth factor (FGF), wingless secreted glycoprotein (WNT) signaling, among others. EMT is a process during which epithelial cells lose their cell polarity and cell-cell adhesion, and acquire migratory and invasive properties to become mesenchymal cells. EMT involves numerous morphological hallmarks of hyperproliferative diseases, like cell plasticity, resistance to apoptosis, dedifferentiation and proliferation, thereby playing a central role during organ fibrosis and cancer progression. EMT was considered as an "all-or-none" process. In contrast to these outdated dichotomist interpretations, recent reports suggest that EMT occurs gradually involving different epithelial cell intermediate states with mesenchyme-like characteristics. These cell intermediate states of EMT differ from each other in their cell plasticity, invasiveness and metastatic potential, which in turn are induced by signals from their microenvironment. EMT is regulated by several transcription factors (TFs), which are members of prominent families of master regulators of transcription. In addition, there is increasing evidence for the important contribution of noncoding RNAs (ncRNAs) to EMT. In our review we highlight articles dissecting the function of different ncRNAs subtypes and nuclear architecture in cell intermediate states of EMT, as well as their involvement in LC and IPF.
SUMMARYIn addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, ... more SUMMARYIn addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support that chromatin opening during tran...
In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractil... more In healing tissue, fibroblasts differentiate to α-smooth muscle actin (SMA)-expressing contractile-myofibroblasts, which pull the wound edges together ensuring proper tissue repair. Uncontrolled expansion of the myofibroblast population may, however, lead to excessive tissue scarring and finally to organ dysfunction. Here, we demonstrate that the loss of low-density lipoprotein receptor-related protein (LRP) 1 overactivates the JNK1/2-c-Jun-Fra-2 signaling pathway leading to the induction of α-SMA and periostin expression in human lung fibroblasts (hLF). These changes are accompanied by increased contractility of the cells and the integrin- and protease-dependent release of active transforming growth factor (TGF)-β1 from the extracellular matrix (ECM) stores. Liberation of active TGF-β1 from the ECM further enhances α-SMA and periostin expression thus accelerating the phenotypic switch of hLF. Global gene expression profiling of LRP1-depleted hLF revealed that the loss of LRP1 affects cytoskeleton reorganization, cell-ECM contacts, and ECM production. In line with these findings, fibrotic changes in the skin and lung of Fra-2 transgenic mice were associated with LRP1 depletion and c-Jun overexpression. Altogether, our results suggest that dysregulation of LRP1 expression in fibroblasts in healing tissue may lead to the unrestrained expansion of contractile myofibroblasts and thereby to fibrosis development. Further studies identifying molecules, which regulate LRP1 expression, may provide new therapeutic options for largely untreatable human fibrotic diseases.
Non-coding RNAs (ncRNAs) are important regulators of different biological processes in the nucleu... more Non-coding RNAs (ncRNAs) are important regulators of different biological processes in the nucleus of the cell as part of the machinery controlling the chromatin structure at specific loci. However, the full extent of the function of ncRNAs in the nucleus has remained elusive, since the involvement of nuclear microRNAs (miRNAs) has not been investigated. Here we deciphered the function of a specific miRNA during transcriptional regulation. We show that the mature miRNA directly binds to nuclear ncRNAs and the RNA exosome complex to induce heterochromatin through histone methyl transferases, SUV39H1 and EZH2, thereby silencing transcription. The mechanism of miRNA/exosome-mediated transcriptional silencing is biologically relevant within the context of transforming growth factor (TGFB1) signaling. Furthermore, we confirmed the mechanism of transcriptional regulation presented here using primary cells from control donors and patients with idiopathic pulmonary fibrosis (IPF), opening new possibilities for the development of novel therapeutic approaches IPF.
Accumulation of mutations causing aberrant changes in the genome promotes cancer. However, mutati... more Accumulation of mutations causing aberrant changes in the genome promotes cancer. However, mutations do not occur in every cancer subtype, suggesting additional events that trigger cancer. Chromatin rearrangements initiated by pioneer factors and architectural proteins are key events occurring before cancer-related genes are expressed. Both protein groups are also master regulators of important processes during embryogenesis. Several publications demonstrated that embryonic gene expression signatures are reactivated during cancer. This review article highlights current knowledge on pioneer factors and architectural proteins mediating chromatin rearrangements, which are the backbone of embryonic expression signatures promoting malignant transformation. Understanding chromatin rearrangements inducing embryonic expression signatures in adult cells might be the key to novel therapeutic approaches against cancers subtypes that arise without genomic mutations.
The eukaryotic cell nucleus consists of functionally specialized subcompartments. These nuclear s... more The eukaryotic cell nucleus consists of functionally specialized subcompartments. These nuclear sub‐compartments are biomolecular aggregates built of proteins, transcripts, and specific genome loci. The structure and function of each nuclear subcompartment are defined by the composition and dynamic interaction between these 3 components. The spatio‐temporal localization of biochemical reactions into membraneless nuclear subcompartments can be achieved through liquid‐liquid phase separation. Based on this organizing principle, nuclear sub‐compartments are droplet‐like structures that adopt spherical shapes, flow, and fuse like liquids or gels. In the present review, we bring into the spotlight seminal works elucidating the functional interactions between scaffold proteins, noncoding RNAs, and genomic loci, thereby inducing liquid‐liquid phase separation as an organizing principle for 3‐dimensional nuclear architecture. We also discuss the implications in different cancer types as well as the potential use of this knowledge to develop novel therapeutic strategies against cancer.—Rubio, K., Dobersch, S., Barreto, G. Functional interactions between scaffold proteins, noncoding RNAs, and genome loci induce liquid‐liquid phase separation as organizing principle for 3‐dimensional nuclear architecture: implications in cancer. FASEB J. 33, 5814–5822 (2019). www.fasebj.org
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