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

  1. Timothy W R Kelso
  2. Devin K Porter
  3. Maria Luisa Amaral
  4. Maxim N Shokhirev
  5. Christopher Benner
  6. Diana C Hargreaves  Is a corresponding author
  1. Salk Institute for Biological Studies, United States
  2. University of California, San Diego, United States

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.

Data availability

The following data sets were generated
The following previously published data sets were used
    1. Stamatoyannopoulos J
    (2010) Stam_HCT-116_1
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM736600).
    1. Allen MA
    2. Galbraith MD
    (2012) GRO-seq from HCT116 cells
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE38140).
    1. ENCODE DCC
    (2012) HudsonAlpha_ChipSeq_HCT-116_FOSL1_(SC-183)_v042211.1
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010756).
    1. ENCODE DCC
    (2012) HudsonAlpha_ChipSeq_HCT-116_CTCF_(SC-5916)_v042211.1
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010903).
    1. ENCODE DCC
    (2012) HudsonAlpha_ChipSeq_HCT-116_ATF3_v042211.1
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010757).
    1. ENCODE DCC
    (2012) HudsonAlpha_ChipSeq_HCT-116_JunD_v042211.1
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010847).
    1. ENCODE DCC
    (2012) GIS-Ruan_ChiaPet_HCT-116_Pol2
    Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM970210).

Article and author information

Author details

  1. Timothy W R Kelso

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Devin K Porter

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maria Luisa Amaral

    The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Maxim N Shokhirev

    The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Christopher Benner

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Diana C Hargreaves

    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    For correspondence
    dhargreaves@salk.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3724-3826

Funding

National Institutes of Health (R00 CA184043-03)

  • Diana C Hargreaves

V Foundation for Cancer Research (V2016-006)

  • Diana C Hargreaves

Genentech Foundation (#G-37246)

  • Timothy W R Kelso

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christopher K Glass, University of California, San Diego, United States

Publication history

  1. Received: July 18, 2017
  2. Accepted: September 28, 2017
  3. Accepted Manuscript published: October 2, 2017 (version 1)
  4. Version of Record published: October 16, 2017 (version 2)

Copyright

© 2017, Kelso et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Timothy W R Kelso
  2. Devin K Porter
  3. Maria Luisa Amaral
  4. Maxim N Shokhirev
  5. Christopher Benner
  6. Diana C Hargreaves
(2017)
Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers
eLife 6:e30506.
https://doi.org/10.7554/eLife.30506
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