Epigenetic Regulation of Neuronal Connectivity and Plasticity in the Brain
Precise temporal and spatial control of gene expression is essential for the development and adaptive responses of the brain. Besides DNA sequence-specific transcription factors, epigenetic factors play crucial roles in the control of gene expression in neurons. Among epigenetic mechanisms, chromatin remodeling enzymes have emerged as key to the regulation of neural circuit assembly and function in the brain. In the lecture, I will review recent findings on the family of chromodomain-helicase-DNA binding (Chd) family of chromatin remodeling enzymes in the control of neuronal morphogenesis and connectivity in the mammalian brain. In particular, I will present recent findings on the functions and mechanisms of Chd4 and associated nucleosome remodeling and deacetylase (NuRD) complex in presynaptic differentiation and dendrite pruning in the mouse cerebellar cortex. Chd4 and the NuRD complex trigger long-term silencing of developmental genes through alterations of histone tail modifications to drive granule neuron parallel fiber presynaptic differentiation in the mouse cerebellum. By contrast, Chd4 dynamically shuts off activity-dependent gene expression via deposition of the histone variant H2A.z at promoters of activity-dependent genes to promote granule neuron dendrite pruning in the mouse cerebellum. These findings suggest that Chd4 employs distinct mechanisms to control fundamental aspects of neuronal connectivity in the brain.
Edison Professor of Neuroscience and Chairman of the Department of Neuroscience
Washington University School of Medicine