Chromatin landscape signals differentially dictate the activities of mSWI/SNF family complexes

Abstract

Mammalian SWI/SNF (mSWI/SNF) adenosine triphosphate–dependent chromatin remodelers modulate genomic architecture and gene expression and are frequently mutated in disease. However, the specific chromatin features that govern their nucleosome binding and remodeling activities remain unknown. We subjected endogenously purified mSWI/SNF complexes and their constituent assembly modules to a diverse library of DNA-barcoded mononucleosomes, performing more than 25,000 binding and remodeling measurements. Here, we define histone modification-, variant-, and mutation-specific effects, alone and in combination, on mSWI/SNF activities and chromatin interactions. Further, we identify the combinatorial contributions of complex module components, reader domains, and nucleosome engagement properties to the localization of complexes to selectively permissive chromatin states. These findings uncover principles that shape the genomic binding and activity of a major chromatin remodeler complex family.

Context-specific chromatin remodeling activity of mSWI/SNF complexes depends on the epigenetic landscape

“…A recent article published in Science reveals how the mammalian SWI/SNF (mSWI/SNF) complexes utilize epigenetic cues in the chromatin landscape for differential chromatin remodeling. 1 The heteromultimeric ATP-dependent SWI/SNF complexes can alter chromatin architecture leading to gene expression modulation (Fig. 1 ).…”

“…Given their implication in numerous diseases, including cancers 3 and neurodevelopmental disorders, 4 the mSWI/SNF or BAF complexes have attracted interest in elucidating their precise action to lend therapeutic ideas. The work of Mashtalir et al 1 has deepened our understanding by decoding the signals which instruct the assembly, localization, and activity of mSWI/SNF complexes. They provide experimental confirmation that the mSWI/SNF complexes depend on single and/or summative histone/nucleosome signatures and subunit modules to determine their activity (Fig.…”

“…Mashtalir et al 1 essentially studied the remodeling activity of mSWI/SNF complexes using a repertoire of (modified) histones and wild-type/mutant histone variant nucleosomes. They purified endogenous final-form mSWI/SNF complexes (cBAF, ncBAF, and PBAF) (Fig.…”

“…A high-throughput quantitative method and advanced 3D view of nucleosome-bound mSWI/SNF complexes afforded systematic observation of mSWI/SNF functional interaction in the chromatin landscape. 1 , 5 Genetic manipulation strategies, including CRISPR-Cas9-mediated gene editing, were employed in studying the contribution of specific subunits or interaction motifs/domains in the differential binding and activity of the mSWI/SNF complexes.…”

“…It is evident from the work of Mashtalir et al 1 that the mSWI/SNF complexes are able to contextualize epigenetic information in the chromatin landscape to regulate their remodeling function on the combinative basis of (i) the presence of specific subunits with reader modules, (ii) nucleosome engagement features, (iii) involvement of core complex modules, and (iv) the resultant complex architecture. Mashtalir et al 1 leveraged the characteristic presence of multiple histone reader domains and subunit dynamics in the mSWI/SNF complexes to dissect the interplay between such histone mark recognition tendencies and modalities for mSWI/SNF complex assembly.…”