BRG1 contributes to the global chromatin accessibility revealed by its acute depletion
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA658358 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12486813_1.fastq.gz | Fastqsanger.gz | |||
| SRR12486813_2.fastq.gz | Fastqsanger.gz | |||
| SRR12486814_1.fastq.gz | Fastqsanger.gz | |||
| SRR12486814_2.fastq.gz | Fastqsanger.gz | |||
| SRR12486815_1.fastq.gz | Fastqsanger.gz |
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Project description:Inositol polyphosphate multikinase (IPMK), a key enzyme in the inositol polyphosphate (IP) metabolism, is a pleiotropic signaling factor involved in major biological events, including transcriptional control. In the yeast, IPMK and its IP products promote the activity of the chromatin-remodeling complex SWI/SNF, which plays a critical role in gene expression by regulating chromatin accessibility. However, the direct link between IPMK and chromatin remodelers remains unclear, raising a question on how IPMK contributes to the transcriptional regulation in mammals. By employing unbiased screening approaches and in vivo/in vitro immunoprecipitations, here we demonstrated that mammalian IPMK physically interacts with the SWI/SNF complex by directly binding to SMARCB1, BRG1, and SMARCC1. Furthermore, we identified the specific domains required for the IPMK-SMARCB1 binding. Notably, using the CUT&RUN and ATAC-seq assays, we discovered that IPMK co-localizes with BRG1 and regulates BRG1 localization as well as BRG1-mediated chromatin accessibility in a genome-wide manner in mouse embryonic stem cells. Finally, our mRNA-seq analyses revealed that IPMK and SMARCB1 regulate the expression of a common gene set, validating a functional link between IPMK and the SWI/SNF complex. Together, these findings show that IPMK regulates promoter-targeting of the SWI/SNF complex and thereby contributes to SWI/SNF-meditated chromatin accessibility, transcription, and differentiation.
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Project description:Deregulation of the chromatin remodeller BRG1 contributes to a wide range of malignancies. In prostate cancer BRG1 is over expressed, however, the underlying function and cellular consequences of this are still being uncovered. Here, we have investigated the role of BRG1 in transcription regulation in prostate cancer. We found that BRG1 is over expressed in both the TCGA prostate cancer cohort as well as a panel of prostate cancer and transformed prostate cell lines. We then utilised a temporal model of BRG1 depletion followed by mRNA-seq to examine changes in gene expression. Surprisingly, we detected a modest overall effect, however, a number of genes associated with proliferation and cell cycle progression were down regulated. We find these genes were in part, co-regulated by AR and FOXA1. Corresponding cell cycle analysis conferred G1 arrest, and altered nuclei morphology with depletion of BRG1. This data provides mechanistic insight into the function of BRG1 in prostate cancer.
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Project description:The SWI/SNF complex remodels chromatin in an ATP-dependent manner through the ATPase subunits BRG1 and BRM. Chromatin remodeling alters nucleosome structure to change gene expression, however aberrant remodeling and gene expression can result in cancer. The function and localization on chromatin of the SWI/SNF complex depends on the protein makeup of the complex. Here we report the protein-protein interactions of wild-type BRG1 or mutant BRG1 in which the HSA domain has been deleted (BRG1-HSA). We demonstrate the interaction of BRG1 with most SWI/SNF complex members and a failure of a number of these members to interact with BRG1-HSA. These results demonstrate that the HSA domain of BRG1 is a critical interaction platform for the correct formation of SWI/SNF remodeling complexes.
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Project description:BRG1-SWI/SNF complex is an important chromatin remodeling complex that involved in various biological processes. Here we described the genome-wide binding of histone acetylation upon BRG1 depletion in mouse embryonic stem cells. Mouse embryonic stem cells were treated with either scrambled siRNA or siRNA against BRG1 for 48 h, and each treatment has three replicates.
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Project description:BRG1-SWI/SNF complex is an important chromatin remodeling complex that involved in various biological processes. Here we described the genome-wide binding of histone acetylation upon BRG1 depletion in human embryonic stem cells. Human embryonic stem cells were treated with either scrambled siRNA or siRNA against BRG1 for 48 h, and each treatment has three replicates.
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Project description:The noncoding Xist RNA recruits silencing factors to the inactive X (Xi) and facilitates re-organization of Xi structure. Here, we examine the epigenomic landscape of the Xi and assess how Xist alters chromatin accessibility. Interestingly, Xist deletion propels selective chromatin re-accessibility on the Xi, affecting various Xi regions differentially. Re-accessibility is regulated by BRG1, an ATPase subunit of SWI/SNF chromatin remodeling complex. In vitro, RNA binding inhibits the nucleosome remodeling and ATPase activities of BRG1. In vivo, Xist directly interacts with BRG1 and expels BRG1 from the Xi. Xist ablation leads to a selective return of BRG1 in cis, emanating from pre-existing BRG1 sites that are Xist-free. BRG1's return correlates with cohesin re-binding and restoration of topologically associated domains (TADs), and results in formation of de novo Xi "superloops." Thus, Xist RNA binding inhibits BRG1's nucleosome remodeling activity and results in expulsion of the SWI/SNF complex from the Xi.
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Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon AP-1 activity.
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Project description:The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription. Here we systematically integrated multi-omics data including ATAC-seq, RNA-seq, WGBS, Hi-C, Cut&Run, CRISPR-Cas9 survival dropout screening, time-solved deep proteomic and phosphoproteomic analyses in cells carrying auxin-induced degron at endogenous CTCF locus. Acute CTCF protein degradation markedly rewired genome-wide chromatin accessibility. Increased accessible chromatin regions were largely located adjacent to CTCF-binding sites at promoter regions and insulator sites and were associated with enhanced transcription of nearby genes. In addition, we used CTCF-associated multi-omics data to establish a combinatorial data analysis pipeline to discover CTCF co-regulatory partners in regulating downstream gene expression. We successfully identified 40 candidates, including multiple established partners (i.e., MYC) supported by all layers of evidence. Interestingly, many CTCF co-regulators (e.g., YY1, ZBTB7A) that have evident alterations of respective downstream gene expression do not show changes at their expression levels across the multi-omics measurements upon acute CTCF loss, highlighting the strength of our system to discover hidden co-regulatory partners associated with CTCF-mediated transcription. This study highlights CTCF loss rewires genome-wide chromatin accessibility, which plays a critical role in transcriptional regulation
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