The SWI/SNF chromatin remodelling complex is required for maintenance of lineage specific enhancers

Abstract

Genes encoding subunits of SWI/SNF (BAF) chromatin remodelling complexes are collectively altered in over 20% of human malignancies, but the mechanisms by which these complexes alter chromatin to modulate transcription and cell fate are poorly understood. Utilizing mouse embryonic fibroblast and cancer cell line models, here we show via ChIP-seq and biochemical assays that SWI/SNF complexes are preferentially targeted to distal lineage specific enhancers and interact with p300 to modulate histone H3 lysine 27 acetylation. We identify a greater requirement for SWI/SNF at typical enhancers than at most super-enhancers and at enhancers in untranscribed regions than in transcribed regions. Our data further demonstrate that SWI/SNF-dependent distal enhancers are essential for controlling expression of genes linked to developmental processes. Our findings thus establish SWI/SNF complexes as regulators of the enhancer landscape and provide insight into the roles of SWI/SNF in cellular fate control.

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

“…S1C). Altogether, our results are consistent with recent reports suggesting association of SWI/SNF with enhancers (Alver et al, 2017; Mathur et al, 2017), supporting the notion that ARID1A also targets a wide spectrum of active genes in mammalian cells (Mathur et al, 2017; Raab et al, 2015; Tolstorukov et al, 2013). …”

“…Previous work suggested a preference for ARID1A and SWI/SNF towards binding enhancer elements (Alver et al, 2017; Mathur et al, 2017, Kelso et al 2017), however, other studies point out a more diffuse and broad distribution of the ARID1 proteins and other SWI/SNF subunits, similar to our observations (Laurette et al, 2015; Morris et al, 2014; Raab et al, 2015). While the SWI/SNF complex is a universal chromatin remodeler in eukaryotes, the role for ARID1A in maintaining accessibility at promoters and enhancers in OCCC is marginal, suggesting that its role in nucleosome positioning may be negligible.…”

“…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.…”

“…ARID1A has been recently proposed to control enhancer acetylation via recruitment of the EP300 acetyltransferase (Alver et al, 2017; Mathur et al, 2017). Our data, however, indicate that the highest occupancy of ARID1A anticorrelates with changes in H3K27ac levels, which are more likely to occur at weak enhancers.…”

“…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.…”