Chromatin landscape dictates remodeling
Large, multicomponent molecular machines known as mammalian SWI/SNF (mSWI/SNF) chromatin-remodeling complexes play critical roles in governing the architecture of our genomes. These entities bind to chromatin (DNA assembled on proteins) inside the nucleus and dictate which regions of DNA, and thus which genes in our genome, are made accessible. It is critical that this process happens at the right times and for the right genes in cells, because disruptions cause diseases such as cancers and neurodevelopmental disorders. Mashtalir et al. uncovered molecular cues that direct complex activities on chromatin, informing specific interactions that may be amenable to therapeutic targeting. This combinatorial approach, which considers many factors involved in determining mSWI/SNF activity, provides a valuable resource for understanding the binding and activity of chromatin-remodeling complexes.
Science, abf8705, this issue p. 306
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.