Distinct silencer states determine epigenetic states of heterochromatin
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE195880 | GEO | 2022/02/08
REPOSITORIES: GEO
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Project description:Distinct silencer states determine epigenetic states of heterochromatin
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Project description:Human silencers have been shown to regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form ‘super-silencers’ and whether they are linked to cancer progression. Here, we show two silencer components of the FGF18 gene can cooperate through compensatory chromatin interactions to form a super-silencer. Double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes in cell identity. To perturb the super-silencers, we applied combinational treatment of an enhancer of zeste homolog 2 inhibitor GSK343, and a repressor element 1-silencing transcription factor inhibitor, X5050 (‘GR’). Interestingly, GR led to severe loss of topologically associated domains and loops, which were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GR synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects in vivo. Overall, our data demonstrated a super-silencer example and showed that GR can disrupt super-silencers, potentially leading to cancer ablation.
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Project description:Cancers arise when particular disease-driving genes adopt abnormal functions, but sequence analyses of coding and regulatory elements leave many of these abnormalities unexplained. We developed a strategy to explore the activities of silencers and enhancers in cancer tumors. Applying the method to human glioblastomas, we produced a driver-gene wide dataset of regulatory elements. Many genes were associated with multiple silencers and enhancers, which cooperatively controlled their expression. Surprisingly, DNA methylation induces enhancers and silencers to acquire new activity setpoints, ranging between strong transcriptional enhancing to strong silencing. Integration of these effects into mathematical models of gene expression resolved the molecular events underlying cancer-genes misregulation in hitherto unexplained tumors. Gene-malfunctioning events due to epigenetically-retuned enhancers or silencers outnumbered causative coding or regulatory sequence alterations, hence dominated driver-genes mutagenesis. The elucidation of this principal gene-transformation mechanism may open the way for methodological disclosing of the driving forces behind cancers and other diseases
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Project description:Cancers arise when particular disease-driving genes adopt abnormal functions, but sequence analyses of coding and regulatory elements leave many of these abnormalities unexplained. We developed a strategy to explore the activities of silencers and enhancers in cancer tumors. Applying the method to human glioblastomas, we produced a driver-gene wide dataset of regulatory elements. Many genes were associated with multiple silencers and enhancers, which cooperatively controlled their expression. Surprisingly, DNA methylation induces enhancers and silencers to acquire new activity setpoints, ranging between strong transcriptional enhancing to strong silencing. Integration of these effects into mathematical models of gene expression resolved the molecular events underlying cancer-genes misregulation in hitherto unexplained tumors. Gene-malfunctioning events due to epigenetically-retuned enhancers or silencers outnumbered causative coding or regulatory sequence alterations, hence dominated driver-genes mutagenesis. The elucidation of this principal gene-transformation mechanism may open the way for methodological disclosing of the driving forces behind cancers and other diseases
2023-10-18 | GSE163019 | GEO
Project description:Subtelomeric chromatin is subject to evolutionarily conserved complex epigenetic regulation and is implicated in numerous aspects of cellular function including formation of heterochromatin, regulation of different stress response pathways, and control of lifespan. Subtelomeric DNA is characterized by the presence of specific repeated segments that serve to propagate silencing activities or to protect chromosomal regions from spreading epigenetic control. Using condition-specific genome wide chromatin immunoprecipitation and expression data, we show that several yeast transcription factors regulate subtelomeric silencing in response to various environmental stimuli through conditional association with proto-silencing regions called X elements. In this context, some factors control the propagation of silencing toward centromeres in response to stimuli affecting stress responses and metabolism, whereas others appear to influence boundaries of silencing, regulating telomere-proximal genes in Y’ elements. The factors implicated here have previously been shown to control adjacent genes at intrachromosomal positions, suggesting dual functionality of the factors and a possible mechanism of coordinating intrachromosomal gene expression with subtelomeric silencing. These data suggest a fundamental mechanism to coordinate telomere biology related to aging and adaptation with cellular environment and the activities of other cellular processes. These are Chip-CHIP data for myc tagged Oaf1p transcription factor from S. cerevisiae grown in the presence or absence of the fatty acid oleate. ChIP-CHIP analysis was performed to determine the genomic distribution of Oaf1p transcription factor in the BY4742 yeast strain after growth in 0.1% glucose, or in the presence of the fatty acid oleate. Three biological replicates for each growth condition (in the presence of low glucose or 5 h after a shift to medium containing oleate as a carbon source). ChIP samples were amplified by PCR, labelled and hybridized to 50-mer tiling arrays covering both strands of the entire yeast genome at a 64 bp resolution.
2011-05-02 | E-GEOD-21852 | biostudies-arrayexpress
Project description:Polycomb (PcG) silencing is crucial for development, but how targets are specified remains incompletely understood. The cold-induced Polycomb Repressive Complex 2 (PRC2) silencing of Arabidopsis thaliana FLOWERING LOCUS C (FLC) provides an excellent system to elucidate PcG regulation. Association of the DNA binding protein VAL1 to the PcG nucleationregion at FLC is an important step. VAL1 interacts with APOPTOSIS AND SPLICING ASSOCIATED PROTEIN (ASAP) complex and PRC1. Here, we show that ASAP and PRC1 are necessary for co-transcriptional repression and chromatin regulation during FLC silencing. ASAP mutants affect FLC transcription in warm conditions, but the rate of FLC silencing in the cold is unaffected. PRC1-mediated H2Aub accumulates at FLC nucleation region during cold, but unlike the PRC2-delivered H3K27me3 does not spread across the locus. H2Aub thus marks the transition to epigenetic silencing, while H3K27me3 is necessary for long-term epigenetic memory. Overall, our work highlights the importance of VAL1 as an assembly platform co-ordinating the co-transcriptional repression and chromatin regulation necessary for the epigenetic silencing of FLC.
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Project description:Interferon-gamma (IFN-gamma) is a key cytokine in response to viral or intracellular bacterial infection in mammals. While a number of enhancers are described to promote IFN-gamma responses, no silencers for the Ifng gene have been identified. By examining H3K4me1 histone modification in naïve CD4+ T cells within Ifng locus, we identified an unrecognized silencer (CNS–28) that is responsible for restraining Ifng expression. Mechanistic study further demonstrates that CNS–28 maintains Ifng silence by diminishing enhancer-promoter interactions within Ifng locus in a T-bet independent manner. Functionally, CNS–28 restrains Ifng transcription in Th1, Tc1, and NK cells during both innate and adaptive immune responses. Moreover, CNS–28 deficiency resulted in repressed type 2 responses due to elevated IFN-gamma expression, shifting Th1 and Th2 paradigm. Thus, CNS–28 activity ensures immune cell quiescence by cooperating with other regulatory cis elements within the Ifng gene locus to minimize autoimmunity.
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Project description:Chromatin immunoprecipitation (ChIP) has been a cornerstone for epigenetic analyses over the last decades, but even coupled to sequencing approaches (ChIP-seq), it is ultimately limited to one protein at a time. In a complementary effort, we here combined ChIP with label-free quantitative (LFQ) mass spectrometry (ChIP-MS) to interrogate local chromatin compositions. We demonstrate the versality of our approach at telomeres, with transcription factors, in tissue and by dCas9-driven locus-specific enrichment.
2024-03-05 | PXD039701 | Pride
Project description:Chromatin immunoprecipitation (ChIP) has been a cornerstone for epigenetic analyses over the last decades, but even coupled to sequencing approaches (ChIP-seq), it is ultimately limited to one protein at a time. In a complementary effort, we here combined ChIP with label-free quantitative (LFQ) mass spectrometry (ChIP-MS) to interrogate local chromatin compositions. We demonstrate the versality of our approach at telomeres, with transcription factors, in tissue and by dCas9-driven locus-specific enrichment.
2024-03-05 | PXD039627 | Pride
Project description:Subtelomeric chromatin is subject to evolutionarily conserved complex epigenetic regulation and is implicated in numerous aspects of cellular function including formation of heterochromatin, regulation of different stress response pathways, and control of lifespan. Subtelomeric DNA is characterized by the presence of specific repeated segments that serve to propagate silencing activities or to protect chromosomal regions from spreading epigenetic control. Using condition-specific genome wide chromatin immunoprecipitation and expression data, we show that several yeast transcription factors regulate subtelomeric silencing in response to various environmental stimuli through conditional association with proto-silencing regions called X elements. In this context, some factors control the propagation of silencing toward centromeres in response to stimuli affecting stress responses and metabolism, whereas others appear to influence boundaries of silencing, regulating telomere-proximal genes in Y’ elements. The factors implicated here have previously been shown to control adjacent genes at intrachromosomal positions, suggesting dual functionality of the factors and a possible mechanism of coordinating intrachromosomal gene expression with subtelomeric silencing. These data suggest a fundamental mechanism to coordinate telomere biology related to aging and adaptation with cellular environment and the activities of other cellular processes. These are Chip-CHIP data for myc tagged Oaf1p transcription factor from S. cerevisiae grown in the presence or absence of the fatty acid oleate.
2011-05-03 | GSE21852 | GEO