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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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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- Chromosomes and Gene Expression
- Evolutionary Biology
Gene regulation is essential for life and controlled by regulatory DNA. Mutations can modify the activity of regulatory DNA, and also create new regulatory DNA, a process called regulatory emergence. Non-regulatory and regulatory DNA contain motifs to which transcription factors may bind. In prokaryotes, gene expression requires a stretch of DNA called a promoter, which contains two motifs called –10 and –35 boxes. However, these motifs may occur in both promoters and non-promoter DNA in multiple copies. They have been implicated in some studies to improve promoter activity, and in others to repress it. Here, we ask whether the presence of such motifs in different genetic sequences influences promoter evolution and emergence. To understand whether and how promoter motifs influence promoter emergence and evolution, we start from 50 ‘promoter islands’, DNA sequences enriched with –10 and –35 boxes. We mutagenize these starting ‘parent’ sequences, and measure gene expression driven by 240,000 of the resulting mutants. We find that the probability that mutations create an active promoter varies more than 200-fold, and is not correlated with the number of promoter motifs. For parent sequences without promoter activity, mutations created over 1500 new –10 and –35 boxes at unique positions in the library, but only ~0.3% of these resulted in de-novo promoter activity. Only ~13% of all –10 and –35 boxes contribute to de-novo promoter activity. For parent sequences with promoter activity, mutations created new –10 and –35 boxes in 11 specific positions that partially overlap with preexisting ones to modulate expression. We also find that –10 and –35 boxes do not repress promoter activity. Overall, our work demonstrates how promoter motifs influence promoter emergence and evolution. It has implications for predicting and understanding regulatory evolution, de novo genes, and phenotypic evolution.
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- Chromosomes and Gene Expression
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The male-specific lethal complex (MSL), which consists of five proteins and two non-coding roX RNAs, is involved in the transcriptional enhancement of X-linked genes to compensate for the sex chromosome monosomy in Drosophila XY males compared with XX females. The MSL1 and MSL2 proteins form the heterotetrameric core of the MSL complex and are critical for the specific recruitment of the complex to the high-affinity ‘entry’ sites (HAS) on the X chromosome. In this study, we demonstrated that the N-terminal region of MSL1 is critical for stability and functions of MSL1. Amino acid deletions and substitutions in the N-terminal region of MSL1 strongly affect both the interaction with roX2 RNA and the MSL complex binding to HAS on the X chromosome. In particular, substitution of the conserved N-terminal amino-acids 3–7 in MSL1 (MSL1GS) affects male viability similar to the inactivation of genes encoding roX RNAs. In addition, MSL1GS binds to promoters such as MSL1WT but does not co-bind with MSL2 and MSL3 to X chromosomal HAS. However, overexpression of MSL2 partially restores the dosage compensation. Thus, the interaction of MSL1 with roX RNA is critical for the efficient assembly of the MSL complex on HAS of the male X chromosome.
