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

Cell Rep. 2021 Nov 2;37(5):109943. doi: 10.1016/j.celrep.2021.109943.

Abstract

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.

Keywords: ARID1A; BAF; EP300; SWI/SNF; cancer; chromatin remodeling; enhancer transcription; nucleosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line
  • Chromatin Assembly and Disassembly
  • DNA-Binding Proteins / deficiency*
  • DNA-Binding Proteins / genetics
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism
  • Male
  • Mice
  • Mice, 129 Strain
  • Mouse Embryonic Stem Cells / metabolism*
  • Nucleosomes / genetics
  • Nucleosomes / metabolism*
  • Precancerous Conditions / genetics
  • Precancerous Conditions / metabolism*
  • Proteolysis
  • Time Factors
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • Transcription, Genetic*
  • Transcriptional Activation*

Substances

  • Arid1a protein, mouse
  • DNA-Binding Proteins
  • Nucleosomes
  • Transcription Factors
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse