Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers

Elife. 2017 Oct 2;6:e30506. doi: 10.7554/eLife.30506.

Abstract

ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here, we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.

Keywords: ARID1A; ARID1B; SWI/SNF complex; chromatin accessibility; chromatin remodeling; chromosomes; epigenetics; genes; human.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Chromatin / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Histones / analysis
  • Humans
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Neoplasms / pathology*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Processing, Post-Translational
  • Synthetic Lethal Mutations*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • ARID1A protein, human
  • ARID1B protein, human
  • Chromatin
  • DNA-Binding Proteins
  • Histones
  • Mutant Proteins
  • Nuclear Proteins
  • Transcription Factors