Diverse Regulation of ISWI Family ATP-dependent Chromatin Remodeling Enzymes by Nucleosome Modifications

Abstract

ATP-dependent chromatin remodelers regulate access to genetic information by controlling nucleosome positions in vivo. However, the mechanism by which remodelers discriminate between different nucleosome substrates is poorly understood. Considering that many chromatin remodeling proteins possess conserved protein domains that interact with nucleosomal features, this study employed a quantitative high-throughput approach, based on use of a DNA-barcoded mononucleosome library, to profile the biochemical activity of human ISWI remodelers in response to a diverse set of nucleosome modifications. The results of this work show that accessory (non-ATPase) subunits of ISWI remodelers can distinguish between differentially modified nucleosomes, directing remodeling activity toward specific nucleosome substrates based on their modification state. Unexpectedly, this investigation led to the discovery that the nucleosome acidic patch is necessary for maximum activity of all ISWI remodelers evaluated, a dependence that also extends to CHD and SWI/SNF family remodelers, suggesting the acidic patch may be generally required for chromatin remodeling. Critically, remodeling activity can be regulated by modifications neighboring the acidic patch, signifying it may act as a tunable interaction hotspot for ATP-dependent chromatin remodelers and, by extension, many other chromatin effectors that engage this region of the nucleosome surface.