Chromatin remodeling inactivates activity genes and regulates neural coding

• Published in: Science (American Association for the Advancement of Science) Vol. 353; no. 6296; pp. 300 - 305
• Main Authors: Yang, Yue, Yamada, Tomoko, Hill, Kelly K., Hemberg, Martin, Reddy, Naveen C., Cho, Ha Y., Guthrie, Arden N., Oldenborg, Anna, Heiney, Shane A., Ohmae, Shogo, Medina, Javier F., Holy, Timothy E., Bonni, Azad
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 15.07.2016; The American Association for the Advancement of Science
• Subjects: Animal behavior; Animals; Brain; Cerebellum; Cerebellum - physiology; Chromatin; Chromatin Assembly and Disassembly; Coding; Dendrites; Dendrites - physiology; Dendritic structure; DNA Helicases - metabolism; Gene Knockout Techniques; Gene Silencing; Genes; Genome-Wide Association Study; Histones; Histones - metabolism; Hypersensitivity; Inactivation; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; Mice; Mice, Knockout; Neurons; Neurons - physiology; Nucleosomes - metabolism; Promoter Regions, Genetic; Pruning; Remodeling; Stimuli; Transcription factors; Transcription, Genetic
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aad4225

Activity-dependent transcription influences neuronal connectivity, but the roles and mechanisms of inactivation of activity-dependent genes have remained poorly understood. Genome-wide analyses in the mouse cerebellum revealed that the nucleosome remodeling and deacetylase (NuRD) complex deposits the histone variant H2A.z at promoters of activity-dependent genes, thereby triggering their inactivation. Purification of translating messenger RNAs from synchronously developing granule neurons (Sync-TRAP) showed that conditional knockout of the core NuRD subunit Chd4 impairs inactivation of activity-dependent genes when neurons undergo dendrite pruning. Chd4 knockout or expression of NuRD-regulated activity genes impairs dendrite pruning. Imaging of behaving mice revealed hyperresponsivity of granule neurons to sensorimotor stimuli upon Chd4 knockout. Our findings define an epigenetic mechanism that inactivates activity-dependent transcription and regulates dendrite patterning and sensorimotor encoding in the brain.