The chromatin remodeling enzyme Chd4 regulates genome architecture in the mouse brain

• Published in: Nature communications Vol. 11; no. 1; pp. 3419 - 14
• Main Authors: Goodman, Jared V., Yamada, Tomoko, Yang, Yue, Kong, Lingchun, Wu, Dennis Y., Zhao, Guoyan, Gabel, Harrison W., Bonni, Azad
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/1; 38/15; 38/22; 38/39; 38/91; 45; 45/90; 49; 631/136; 631/208/200; 631/337/100/101; 631/337/100/102; 631/378; Accessibility; Animals; Architecture; Brain; Brain - metabolism; Brain architecture; Cell Cycle Proteins - metabolism; Cerebellum; Chromatin - metabolism; Chromatin Assembly and Disassembly; Chromatin remodeling; Chromosomal Proteins, Non-Histone - metabolism; Chromosomes, Mammalian - metabolism; Cohesin; Cohesins; DNA Helicases - genetics; DNA Helicases - metabolism; Enhancer Elements, Genetic - genetics; Enhancers; Enzymes; Epigenesis, Genetic; Gene expression; Gene regulation; Genome; Genomes; Granular materials; Granule cells; Humanities and Social Sciences; Mice, Knockout; Models, Genetic; multidisciplinary; Neurons; Occupancy; Protein Binding; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17065-z

The development and function of the brain require tight control of gene expression. Genome architecture is thought to play a critical regulatory role in gene expression, but the mechanisms governing genome architecture in the brain in vivo remain poorly understood. Here, we report that conditional knockout of the chromatin remodeling enzyme Chd4 in granule neurons of the mouse cerebellum increases accessibility of gene regulatory sites genome-wide in vivo. Conditional knockout of Chd4 promotes recruitment of the architectural protein complex 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 role for chromatin remodeling in the control of genome architecture organization in the mammalian brain. The mechanisms underlying gene regulation and genome architecture remain poorly understood. Here, the authors investigate the role of chromatin remodelling enzyme Chd4 in granule neurons of the mouse cerebellum and find that conditional knockout of Chd4 preferentially activates enhancers and modulates genome architecture at a genome-wide level.