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

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