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.
Reviewing Editor
- Christopher K Glass, University of California, San Diego, United States
Version history
- Received: July 18, 2017
- Accepted: September 28, 2017
- Accepted Manuscript published: October 2, 2017 (version 1)
- 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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Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers
eLife 6:e30506.
https://doi.org/10.7554/eLife.30506
Further reading
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Extrachromosomal DNA is a common cause of oncogene amplification in cancer. The non-chromosomal inheritance of ecDNA enables tumors to rapidly evolve, contributing to treatment resistance and poor outcome for patients. The transcriptional context in which ecDNAs arise and progress, including chromosomally-driven transcription, is incompletely understood. We examined gene expression patterns of 870 tumors of varied histological types, to identify transcriptional correlates of ecDNA. Here, we show that ecDNA-containing tumors impact four major biological processes. Specifically, ecDNA-containing tumors up-regulate DNA damage and repair, cell cycle control, and mitotic processes, but down-regulate global immune regulation pathways. Taken together, these results suggest profound alterations in gene regulation in ecDNA-containing tumors, shedding light on molecular processes that give rise to their development and progression.
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ASARs are a family of very-long noncoding RNAs that control replication timing on individual human autosomes, and are essential for chromosome stability. The eight known ASAR lncRNAs remain closely associated with their parent chromosomes. Analysis of RNA-protein interaction data (from ENCODE) revealed numerous RBPs with significant interactions with multiple ASAR lncRNAs, with several hnRNPs as abundant interactors. An ~7 kb domain within the ASAR6-141 lncRNA shows a striking density of RBP interaction sites. Genetic deletion and ectopic integration assays indicate that this ~7 kb RNA binding protein domain contains functional sequences for controlling replication timing of entire chromosomes in cis. shRNA-mediated depletion of 10 different RNA binding proteins, including HNRNPA1, HNRNPC, HNRNPL, HNRNPM, HNRNPU, or HNRNPUL1, results in dissociation of ASAR lncRNAs from their chromosome territories, and disrupts the synchronous replication that occurs on all autosome pairs, recapitulating the effect of individual ASAR knockouts on a genome-wide scale. Our results further demonstrate the role that ASARs play during the temporal order of genome-wide replication, and we propose that ASARs function as essential RNA scaffolds for the assembly of hnRNP complexes that help maintain the structural integrity of each mammalian chromosome.
