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

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.

The Tumor Suppressor ARID1A Controls Global Transcription via Pausing of RNA Polymerase II

“…Next, we measured changes in accessibility and transcription upon depletion of ARID1A. Previous reports postulate that ARID1A may specifically modulate a subset of enhancers (Kelso et al, 2017), however our ChIP-seq analysis (Fig. 1) suggests a widespread role of ARID1A at most protein coding genes.…”

“…We clustered enhancers into two categories based on H3K27ac level: i) weak enhancers (quartiles 1 and 2 of H3K27ac intensity) and ii) strong enhancers (H3K27ac quartiles 3 and 4). While we observed loss of accessibility at cis-regulatory elements (Kelso et al, 2017), this effect was largely confined to weak enhancers (Fig. 2C) that are poorly bound by ARID1A (Fig.…”

“…Next, to determine if ARID1A depletion changes the chromatin status of its target genes and enhancers, we performed ChIP-seq of H3K27ac. Previous reports suggest that ARID1A depletion leads to loss of acetylation at enhancers (Alver et al, 2017; Kelso et al, 2017; Mathur et al, 2017). Consistent with these findings, we observed moderate but significant decrease of H3K27ac across enhancers ( p < 2.2 × 10 −16 ; Supplemental Fig.…”

“…Importantly, the large majority of ARID1A mutations are frameshift indels or nonsense point mutations resulting in functional loss of the entire protein (Ayhan et al, 2012; Jones et al, 2010). Recent studies have proposed ARID1A as regulator of H3 acetylation (H3K27ac) (Alver et al, 2017; Mathur et al, 2017) and chromatin accessibility (Kelso et al 2017) at distal enhancer regions. Using a model of OCCC, we examine the immediate consequences of ARID1A loss on transcription and nucleosome positioning.…”

Glioma tumor suppressor candidate region gene 1 (GLTSCR1) and its paralog GLTSCR1-like form SWI/SNF chromatin remodeling subcomplexes

“…The different BAF complexes containing these two paralogs share many of their genomic targets; however, they also bind unique genomic targets and deletions are non-synonymous for gene regulation (20). ARID1A is the most commonly mutated SWI/SNF subunit in cancer, due to transcriptional functions that are non-redundant with ARID1B (21,22); however, cancers with deletions in ARID1A are dependent on ARID1B for viability (23) due to redundant, essential functions at enhancers (22). Additionally, homologous complexes can display transcriptionally antagonistic roles, as has been observed for ARID1A and ARID2-containing complexes at specific gene targets (8,20,24).…”