Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers
- Salk Institute for Biological Studies, United States
- 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
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ARID1A and ARID1B loss in HCT116 and TOV21G cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE101975).
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Stam_HCT-116_1Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM736600).
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ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE71514).
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GRO-seq from HCT116 cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE38140).
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HudsonAlpha_ChipSeq_HCT-116_FOSL1_(SC-183)_v042211.1Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010756).
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HudsonAlpha_ChipSeq_HCT-116_CTCF_(SC-5916)_v042211.1Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010903).
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HudsonAlpha_ChipSeq_HCT-116_ATF3_v042211.1Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010757).
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HudsonAlpha_ChipSeq_HCT-116_JunD_v042211.1Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM1010847).
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Human ovarian tumors and normal ovariesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE6008).
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GIS-Ruan_ChiaPet_HCT-116_Pol2Publicly available at the NCBI Gene Expression Omnibus (accession no: GSM970210).
Article and author information
Author details
Diana C Hargreaves
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.
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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