Dynamic cohesin is required for lineage specific distal gene regulation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA557678 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12623450.fastq.gz | Fastqsanger.gz | |||
| SRR12623451.fastq.gz | Fastqsanger.gz | |||
| SRR12623452.fastq.gz | Fastqsanger.gz | |||
| SRR12623453.fastq.gz | Fastqsanger.gz | |||
| SRR12623454.fastq.gz | Fastqsanger.gz |
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Project description:The cohesin complex plays essential roles in sister chromatin cohesin, chromosome organization and gene expression. The role it plays in the regulation of genes is incompletely understood. Here, we report that the cohesin release factor WAPL in mouse embryonic stem cells is crucial for maintaining a pool of dynamically bound cohesin to regions in the genome that are associated with lineage specific genes. These regions are enriched for active enhancer marks and transcription factor binding sites. Stabilization of cohesin, which leads to a loss of dynamic cohesin from these regions does not affect transcription factor binding or active enhancer marks, but does result in changes in promoter-enhancer interactions and downregulation of genes. Acute cohesin depletion can phenocopy the effect of WAPL depletion, showing that cohesin plays a crucial role in maintaining expression of lineage specific genes. The binding of dynamic cohesin to chromatin is dependent on the pluripotency transcription factor OCT4, but not NANOG. Finally, sites of dynamic cohesin binding sites are also found in differentiated cells, suggesting that they represent a general regulatory principle. We propose that the binding of dynamic cohesin to regulatory sites creates a favorable spatial environment in which promoters and enhancers can communicate to ensure proper gene expression.
2020-10-15 | GSE135180 | GEO
Project description:Lymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs. How this occurs remains unclear. Herein, we demonstrate that in small pre-B cells, the lineage and stage-specific epigenetic reader BRWD1 reorders three-dimensional chromatin topology to affect transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters and coordinated this with Igk locus contraction. BRWD1 did so by converting chromatin-bound static cohesin to dynamic complexes competent to mediate long-range looping. Remarkably, ATP depletion recapitulated cohesin distributions observed in Brwd1-/- cells. Therefore, in small pre-B cells, cohesin conversion appears to be the main energetic mechanism dictating where dynamic looping occurs in the genome. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be regulated by lineage contextual mechanisms to facilitate specific cell fate transitions.
2023-08-31 | GSE221518 | GEO
Project description:Lymphocyte development consists of sequential and mutually exclusive cell states of proliferative selection and antigen receptor gene recombination. Transitions between each state require large, coordinated changes in epigenetic landscapes and transcriptional programs. How this occurs remains unclear. Herein, we demonstrate that in small pre-B cells, the lineage and stage-specific epigenetic reader BRWD1 reorders three-dimensional chromatin topology to affect transition between proliferative and gene recombination molecular programs. BRWD1 regulated the switch between poised and active enhancers interacting with promoters and coordinated this with Igk locus contraction. BRWD1 did so by converting chromatin-bound static cohesin to dynamic complexes competent to mediate long-range looping. Remarkably, ATP depletion recapitulated cohesin distributions observed in Brwd1-/- cells. Therefore, in small pre-B cells, cohesin conversion appears to be the main energetic mechanism dictating where dynamic looping occurs in the genome. Our findings provide a new mechanism of cohesin regulation and reveal how cohesin function can be regulated by lineage contextual mechanisms to facilitate specific cell fate transitions.
2023-08-31 | GSE221517 | GEO
Project description:The cohesin complex consists of multiple core subunits that play critical roles in mitosis and transcriptional regulation. The cohesin-associated protein Wapal plays a central role in offloading cohesin to facilitate sister chromatid separation, but its role in regulating mammalian gene expression is not understood. We used embryonic stem cells (ESCs) as a model given the well-defined transcriptional regulatory circuits established through master transcription factors and epigenetic pathways that regulate their ability to maintain a pluripotent state. RNAi-mediated depletion of Wapal causes a loss of pluripotency, phenocopying loss of core cohesin subunits. Using chromatin immunoprecipitation coupled with next-generation sequencing (ChIP-seq) we determine that Wapal occupies genomic sites distal to genes in combination with CTCF and core cohesin subunits such as Rad21. Interestingly, genomic sites occupied by Wapal appear enriched for cohesin, implying Wapal does not offload cohesin at regions it occupies. Wapal depletion induces derepression of Polycomb Group (PcG) target genes without altering total levels of Polycomb-mediated histone modifications, implying that PcG enzymatic activity is preserved. By integrating ChIP-seq and gene expression changes data we identify that Wapal binding is enriched at the promoters of PcG silenced genes and is required for proper Polycomb Repressive Complex 2 (PRC2) recruitment. Lastly, we demonstrate that Wapal is required for the interaction of a distal cis-regulatory element (CRE) with the c-Fos promoter. Collectively, this work indicates that Wapal plays a critical role in silencing of PcG target genes through the interaction of distal CREs with promoters.
2016-03-21 | GSE78826 | GEO
Project description:The Cohesin complex critically controls interactions between proximal and distal cis-regulatory elements, while Cohesin disruption causes improper gene activation. This process associates with biased hematopoiesis, and Cohesin mutations are common in myeloid neoplasia. In this study, we initially explore Cohesin-associated dynamics and regulation of hematopoietic stem cell renewal and erythropoiesis. Cohesin binding to chromatin increases during erythroid differentiation at active promoters and enhancers only, with pre-binding of Etv6 predicting the subsequent dynamics of Cohesin binding at these elements. Etv6 also binds with the Cohesin complex at chromatin during haematopoiesis. Perturbation of Cohesin members does not alter hematopoietic self-renewal, but severely impairs erythroid differentiation. As in normal erythroid differentiation, the strongest impairment of gene activation in Cohesin-perturbed erythropoiesis occurs at Etv6-pre-bound loci. Taken together these findings propose a mechanism for how the Cohesin complex regulates the induction of gene expression during differentiation and how this may be perturbed in myeloid malignancies.
2019-04-09 | GSE129478 | GEO
Project description:In this study we show that depletion of the cohesin subunit SMC3 or the Mediator subunit MED12 significantly impairs the ERα-regulated transcriptome. Surprisingly, SMC3 depletion appears to elicit this effect indirectly by rapidly decreasing ESR1 transcription and ERα protein levels. Moreover, we provide evidence that both SMC3 and MED12 colocalize on the ESR1 gene and are mutually required for occupancy as well as for transcriptional elongation. Finally, we show that extended proteasome inhibition decreases the mRNA expression of cohesin subunits which accompanies a decrease in ESR1 mRNA and ERα protein levels as well as estrogen-regulated transcription. Conclusions: These results identify the ESR1 gene as a cohesin/Mediator-dependent gene and indicate that this regulation may potentially be exploited for the treatment of estrogen-dependent breast cancer. This set contains 18 microarray samples with triplicates for each condition. 3 control siRNA, 3 control estrogen stimulated, 3 siRNA Med12 knockdown, 3 siRNA Med12 knockdown estrogen stimulated, 3 siRNA Smc3 knockdown, 3 siRNA Smc3 knockdown estrogen stimulated.
2013-05-20 | E-GEOD-38252 | biostudies-arrayexpress
Project description:We found binding of the remodeling protein BRG1 was programmed by lineage and activation signals. BRG1 binding was positively correlated with gene activity at protein-coding and miRNA genes. BRG1 binding was found at promoters and distal regions, including known and novel distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites possessed enhancer activity, suggesting a general role for BRG1 in long-distance gene regulation. Together, these findings suggest BRG1 interprets differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings indicate BRG1 binding is a useful marker for identifying cis-regulatory regions in protein-coding and miRNA genes. Compare BRG1 binding in T helper subsets genome wide; Naïve, resting Th1, resting Th2, Stimulated Th1, Stimulated Th2, Stimulated Th17, compared to input DNA as negative control
2011-03-01 | E-GEOD-23719 | biostudies-arrayexpress
Project description:Cohesin-dependent regulation of dynamic gene expression during differentiation is lost in Cohesin-mutated myeloid malignancies
| PRJNA531471 | ENA
Project description:Chromatin undergoes major remodeling around DNA double strand breaks (DSB) to promote repair and DNA damage response (DDR) activation. We recently reported a high resolution map of gammaH2AX around multiple breaks on the human genome, using a new cell-based DSB inducible system. In an attempt to further characterize the chromatin landscape induced around DSBs, we now report the profile of SMC3, a subunit from the cohesin complex, previously characterized as required for repair by homologous recombination. We found that the recruitment of cohesin is moderate and restricted to the immediate vicinity of DSBs. In addition, we show that the cohesin complex, which was also recently proposed to be a key player in chromosome organisation and chromatin looping, controls gammaH2AX distribution within domains. Indeed, as we reported for transcription, cohesin binding antagonizes gammaH2AX spreading. Remarkably, depletion of cohesin leads to an increase of gammaH2AX at cohesin-bound genes (revelead by gammaH2AX mapping in upon SCC1 siRNA), associated with a decrease in their expression level after DSB induction. Thus our study identifies a novel role for the cohesin complex in protecting the genes located in gammaH2AX domains from both gammaH2AX spreading and transcriptional shut-down after DSB induction.
2012-01-01 | E-TABM-1164 | biostudies-arrayexpress
Project description:We found binding of the remodeling protein BRG1 was programmed by lineage and activation signals. BRG1 binding was positively correlated with gene activity at protein-coding and miRNA genes. BRG1 binding was found at promoters and distal regions, including known and novel distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites possessed enhancer activity, suggesting a general role for BRG1 in long-distance gene regulation. Together, these findings suggest BRG1 interprets differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings indicate BRG1 binding is a useful marker for identifying cis-regulatory regions in protein-coding and miRNA genes.
2011-03-01 | GSE23719 | GEO