Chromatin Remodeling Regulates Genome Architecture in the Brain

The development and function of the brain require exquisite control of gene expression. Genome architecture is thought to play a critical regulatory role in gene expression, but the mechanisms that govern genome architecture in the brain in vivo have remained poorly understood. Here, we report that conditional knockout of the chromatin remodeling enzyme Chd4 in granule neurons of the mouse cerebellum increases on a genome-wide level the accessibility of gene regulatory sites in vivo. Strikingly, conditional knockout of Chd4 also promotes recruitment of the architectural protein Cohesin preferentially to gene enhancers in granule neurons in vivo. Importantly, in vivo profiling of genome architecture reveals that conditional knockout of Chd4 strengthens interactions among developmentally repressed contact domains as well as genomic loops in a manner that tightly correlates with increased accessibility, enhancer activity, and Cohesin occupancy at these sites. Collectively, our findings define a novel role for chromatin remodeling in the control of genome architecture organization in the mammalian brain.