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

ABSTRACT: Summary The ARID1A subunit of SWI/SNF chromatin remodeling complexes is a potent tumor suppressor. Here, a degron is applied to detect rapid loss of chromatin accessibility at thousands of loci where ARID1A acts to generate accessible minidomains of nucleosomes. Loss of ARID1A also results in the redistribution of the coactivator EP300. Co-incident EP300 dissociation and lost chromatin accessibility at enhancer elements are highly enriched adjacent to rapidly downregulated genes. In contrast, sites of gained EP300 occupancy are linked to genes that are transcriptionally upregulated. These chromatin changes are associated with a small number of genes that are differentially expressed in the first hours following loss of ARID1A. Indirect or adaptive changes dominate the transcriptome following growth for days after loss of ARID1A and result in strong engagement with cancer pathways. The identification of this hierarchy suggests sites for intervention in ARID1A-driven diseases. Graphical abstract Highlights • Degradation of ARID1A disrupts nucleosomes flanking pluripotency transcription factors• EP300 is rapidly redistributed with increased occupancy adjacent to upregulated genes• These changes are associated with misregulation of a few hundred genes within 2 h• During subsequent days, widespread indirect changes mimic a premalignant state Blümli et al. show that degradation of ARID1A reorganizes nucleosomes flanking pluripotency transcription factors and causes redistribution of the coactivator EP300. Lost EP300 at enhancers is associated with downregulation of transcription and gained EP300 with upregulation. Few genes are directly affected, but widespread indirect effects accumulate slowly to phenocopy premalignancy.

SUBMITTER: Blumli S 

PROVIDER: S-EPMC8578704 | biostudies-literature |

REPOSITORIES: biostudies-literature