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Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

ABSTRACT: The ARID1A subunit of the SWI/SNF chromatin remodelling complex is one of the most frequently mutated tumour suppressors. Here, a degron system is applied to detect rapid loss of chromatin accessibility at thousands of loci that frequently include binding sites for pluripotency transcription factors where ARID1A acts to generate accessible mini domains of nucleosomes. At a subset of these locations, the histone acetyltransferase EP300 dissociates and histone H3K27 acetylation decreases. Genes adjacent to these sites are frequently downregulated. Remarkably, dissociation of EP300 in the absence of chromatin changes is linked to rapid transcriptional upregulation. Sites where EP300 exhibits co-repressor activity are enriched for MLL3-4, BRD4 and RNA polymerase. A few genes directly affected by these pathways are associated with cancer and pluripotency pathways that come to dominate the chronic ARID1A phenotype. This suggests a handful of upstream regulators drive adaption and represent new sites for intervention in ARID1A driven diseases.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Embryonic Stem Cell

SUBMITTER: Nicola Wiechens

LAB HEAD: Tom Owen-Hughes

PROVIDER: PXD021636 | Pride | 2021-11-02

REPOSITORIES: Pride

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			Action	DRS
	DeamidationNQSites.txt	Txt
	NWiechens190730TMT_v1623.sps	Other
	NWiechens_190730_FR01.raw	Raw
	NWiechens_190730_FR02.raw	Raw
	NWiechens_190730_FR03.raw	Raw

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Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

Project description:The ARID1A subunit of the SWI/SNF chromatin remodelling complex is one of the most frequently mutated tumour suppressors. Here, a degron system is applied to detect rapid loss of chromatin accessibility at thousands of loci that frequently include binding sites for pluripotency transcription factors where ARID1A acts to generate accessible mini domains of nucleosomes. At a subset of these locations, the histone acetyltransferase EP300 dissociates and histone H3K27 acetylation decreases. Genes adjacent to these sites are frequently downregulated. Remarkably, dissociation of EP300 in the absence of chromatin changes is linked to rapid transcriptional upregulation. Sites where EP300 exhibits co-repressor activity are enriched for MLL3-4, BRD4 and RNA polymerase. A few genes directly affected by these pathways are associated with cancer and pluripotency pathways that come to dominate the chronic ARID1A phenotype. This suggests a handful of upstream regulators drive adaption and represent new sites for intervention in ARID1A driven diseases.

2021-11-02 | PXD021623 | Pride

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

2021-11-02 | PXD021631 | Pride

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription.

2021-11-02 | PXD021624 | Pride

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for EP300 dependent activation and repression of transcription

2021-11-02 | PXD021824 | Pride

Genome-wide analysis of effects of ARID1A depletion in mouse embryonic stem cells

Project description:A degron system is used to deplete ARID1A a subunit of the SWI/SNF complex in mouse embryonic stem cells. Genome wide analysis of chromatin accessibility (ATAC-seq), nucleosome posistioning (MNase-seq), nascent transcription (TT-seq), binding to EP300 and presence of histone H3 K27acetylation (ChIP-seq) amd histone H3K27 tria-methylation (ChIP-seq) allowed us to identify two different pathways responsible for the up and downregulation of transcription following the loss of ARID1A. The rapid depletion of ARID1A generates mini domains of nucleomes at pluripotency transcription factor binding sites. Loss of ARID1A also results in the redistribution of the co-activator EP300. Locations of co-incident EP300 dissociation and lost chromatin accessibility occur adjacent to rapidly downregulated genes. Promoter proximal regions that gain EP300 are linked to genes that are transcriptionally upregulated. Our findings illustrate the importance of both direct and indirect effects in causing rapid changes to gene expression. Only a few genes are directly affected after ARID1A depletion and contribute to pathways associated with cancer and pluripotency establishing the loss of ARID1A phenotype.

2021-10-24 | GSE183278 | GEO

ARID1A regulates chromatin organization and establishment of epigenetic marks for DSB repair and transcription silencing

Project description:AT-rich interactive domain-containing protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. ARID1A contributes to DNA damage response pathways, and we previously reported that ARID1A loss is associated with mutational signatures linked to DNA repair defects. Here we show that ARID1A is promoting both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates the chromatin loop formation at DSB sites by interacting with the cohesin subunit RAD21 and CTCF insulator protein promoting their enrichment around the DSBs. Further analysis demonstrates that ARID1A’s involvement in DSB repair is accompanied by alterations of chromatin accessibility and distribution of activating histone marks at DSBs. ARID1A binds to and promotes the recruitment of the HDAC1 to control transcription repression at these DSBs. Altogether, ARID1A simultaneously regulates DSB repair and transcription silencing in transcriptionally active chromatin. ARID1A depletion resulted in defective DSB repair, which subsequently led to accumulation of micronuclei, activation of cGAS-STING pathway and an increased expression of immunomodulatory cytokines and chemokines upon IR treatment. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and can estimate the levels of tumor-infiltrating immune cells and response to combination of radio- and immunotherapy.

2024-06-22 | PXD047225 | Pride

Targeting EZH2 methyltransferase activity in ARID1A mutated cells as a synthetic lethal therapeutic strategy

Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.

2015-01-20 | E-GEOD-54979 | biostudies-arrayexpress

Inability to switch from ARID1A-BAF to ARID1B-BAF impairs exit from pluripotency and commitment towards neural crest formation in ARID1B-related neurodevelopmental disorders

Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.

2021-10-12 | PXD028557 | Pride

ARID1A RIME in human cell lines and tissue xenografts.

Project description:Examination of chromatin-bound proteins associated with ARID1A, BRG1 and ERa in MCF7 cells and ERa in ER+ patient-derived xenografts using RIME protocol and mass spectrometry.

2019-10-31 | PXD011810 | Pride

mRNA-seq for HCT116 Parental and ARID1A knockdown cells, mRNA-seq for DLD1 Parental, ARID1A knockdown and ARID1A knockout cells, mRNA-seq for COLO320DM Parental and ARID1A knockdown and ARID1A knockout cells

Project description:The study identifies genes that are regulated by the loss of the chromatin remodeller subunit ARID1A in colorectal cancer cell lines. This gene is frequently mutated in colorectal cancer.

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