Autism spectrum disorders (ASDs) are complex diseases regulated by genetic and epigenetic factors with synaptic dysfunction as a center defect. Many ASD-associated genes encode either proteins directly functioning in synapse or regulators of synaptic genes. By modulating chromatin structure and modifications, epigenetic regulators function together with transcription factors to direct gene expression in response to developmental and environmental signals. Recently, the ATP-dependent chromatin remodeling BAF complexes have been linked to ASDs. Mutations in genes encoding several BAF subunits including the core ATPase subunit Brg1 cause diseases with autistic symptoms. Recent large-scale genomic studies predicted BAF core subunit Brg1 (also known as SmarcA4) as one of the key nodes of the ASD gene network. My previous studies have identified a mammalian neuron specific BAF (nBAF) complex, which plays an essential role in activity-induced dendritic growth, suggesting a Ca2+ signaling induced chromatin regulation of gene expression. Recent studies in my lab demonstrated that Brg1 is required for synapse development and maturation. We found that Brg1 is required for dendritic spine/synapse elimination mediated by the ASD- associated transcription factor MEF2C and that Brg1 regulates the activity-induced expression of a specific subset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interacts with MEF2 and that MEF2 is required for Brg1 recruitment to target genes in response to neuron activation. Our genomic and proteomic data further suggest that Brg1 is activated by neuronal activities and recruited to enhancers by both MEF2 and active histone modifications. We hypothesize that Brg1 undergoes activity- dependent modification changes and coordinates with MEF2 and dynamic epigenetic complexes to specifically regulate target gene activation and synapse plasticity. In the proposal, we will determine (1) how Brg1 is recruited by transcription factors and epigenetic marks in response to neuronal activation, (2) how Brg1 is activated by neuronal activities and regulate target gene transcription, and (3) how Brg1 regulates neuronal gene expression and synaptic plasticity induced by physiological levels of activities. Our studies will provide mechanistic insights to the epigenetic regulation of normal neuronal development and impact on neurological diseases such as ASD.
Autism spectrum disorders (ASDs) are complex diseases regulated by genetic and epigenetic factors with synaptic dysfunction as a center defect. The goal of this study is to elucidate the role of an ASD-linked epigenetic regulator Brg1/Smarca4 in regulating neuronal gene expression and synapse plasticity in response to neuronal activities. Our studies will provide novel insights into the epigenetic regulation of activity-induced gene expression during synaptogenesis and may provide new therapeutic strategies for ASDs.
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