A novel ATAC-seq approach reveals lineage-specific reinforcement of the open chromatin landscape via cooperation between BAF and p63

Abstract

BackgroundOpen chromatin regions are correlated with active regulatory elements in development and are dysregulated in diseases. The BAF (SWI/SNF) complex is essential for development, and has been demonstrated to remodel reconstituted chromatin in vitro and to control the accessibility of a few individual regions in vivo. However, it remains unclear where and how BAF controls the open chromatin landscape to regulate developmental processes, such as human epidermal differentiation.ResultsUsing a novel “on-plate” ATAC-sequencing approach for profiling open chromatin landscapes with a low number of adherent cells, we demonstrate that the BAF complex is essential for maintaining 11.6 % of open chromatin regions in epidermal differentiation. These BAF-dependent open chromatin regions are highly cell-type-specific and are strongly enriched for binding sites for p63, a master epidermal transcription factor. The DNA sequences of p63 binding sites intrinsically favor nucleosome formation and are inaccessible in other cell types without p63 to prevent ectopic activation. In epidermal cells, BAF and p63 mutually recruit each other to maintain 14,853 open chromatin regions. We further demonstrate that BAF and p63 cooperatively position nucleosomes away from p63 binding sites and recruit transcriptional machinery to control tissue differentiation.ConclusionsBAF displays high specificity in controlling the open chromatin landscape during epidermal differentiation by cooperating with the master transcription factor p63 to maintain lineage-specific open chromatin regions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0840-9) contains supplementary material, which is available to authorized users.

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

“…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. Previous studies describe a role for SWI/SNF components (especially BRG1) as modulators of accessibility at enhancers (Bao et al, 2015; Laurette et al, 2015), but we find that the contribution of ARID1A is limited to the weakest enhancer regions, displaying the lowest enrichment for ARID1A by ChIP-seq. Similarly, promoter accessibility is regulated by the BRG1 and SNF subunits of SWI/SNF (Tolstorukov et al, 2013), but is not affected by ARID1A according to our ATAC-seq analysis.…”

“…While the AT-rich interactive domain (ARID) has been shown to bind DNA in vitro (Kortschak et al, 2000; Wilsker et al, 2004), the function of ARID1A and ARID1B in vivo is poorly understood. ARID1A and ARID1B are components of the BAF sub-family of SWI/SNF complexes, in association with the BRG1/BRM ATPases that maintain accessibility at most promoters and enhancers (Bao et al, 2015; Tolstorukov et al, 2013). There are limited genome-wide studies on ARID1A and ARID1B, which suggest substantial overlap of their target loci but functionally distinct roles (Raab et al, 2015).…”

The Many Roles of BAF (mSWI/SNF) and PBAF Complexes in Cancer

“…BAF complexes have many roles in development (Ho and Crabtree 2010); the presence of BAF complexes on chromatin correlates with enhancers (Rada-Iglesias et al 2011), and its activity regulates a variety of important biological processes ranging from self-renewal and pluripotency in embryonic stem cells (Ho et al 2009b), to cardiac development (Lickert et al 2004), and neural differentiation (Yoo et al 2009). BAF activity and transcription factor (TF) binding appear to be coupled idiosyncratically, as examples can be found where TF binding requires BAF activity (Ho et al 2011; Bao et al 2015) or, alternatively, where recruitment of BAF requires existing TF binding (Liu et al 2001). Some of the complexes’ subunits are tissue-specific; for example, BAF53B (ACTL6B), BAF45B (DPF1), and SS18L1 (CREST, a Ca2+-responsive regulator), are found only in BAF complexes of mature, post-mitotic neurons (Olave et al 2002; Aizawa et al 2004; Lessard et al 2007; Staahl et al 2013).…”

ATP-dependent chromatin remodeling during mammalian development

“…In the absence of BAF53A, the BAF complex binds to epidermal differentiation genes to facilitate their expression. BAF complexes also coordinate with the epidermal differentiation transcription factor P63 to maintain an open chromatin state at P63 binding sites, facilitating the expression of epidermal differentiation-specific genes in keratinocytes (Bao et al, 2015). BRG1 also has an important role during melanocyte development .…”