Autism spectrum disorders (ASDs) are complex diseases regulated by genetic and epigenetic factors withsynaptic dysfunction as a center defect. Many ASD-associated genes encode either proteins directlyfunctioning 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 todevelopmental and environmental signals. Recently, the ATP-dependent chromatin remodeling BAFcomplexes have been linked to ASDs. Mutations in genes encoding several BAF subunits including the coreATPase subunit Brg1 cause diseases with autistic symptoms. Recent large-scale genomic studies predictedBAF core subunit Brg1 (also known as SmarcA4) as one of the key nodes of the ASD gene network. Myprevious studies have identified a mammalian neuron specific BAF (nBAF) complex, which plays an essentialrole in activity-induced dendritic growth, suggesting a Ca2+ signaling induced chromatin regulation of geneexpression. Recent studies in my lab demonstrated that Brg1 is required for synapse development andmaturation. 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 specificsubset of genes that overlap significantly with the targets of MEF2. Our analyses showed that Brg1 interactswith 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 toenhancers 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 specificallyregulate target gene activation and synapse plasticity. In the proposal, we will determine (1) how Brg1 isrecruited by transcription factors and epigenetic marks in response to neuronal activation, (2) how Brg1 isactivated by neuronal activities and regulate target gene transcription, and (3) how Brg1 regulates neuronalgene expression and synaptic plasticity induced by physiological levels of activities. Our studies will providemechanistic insights to the epigenetic regulation of normal neuronal development and impact on neurologicaldiseases such as ASD.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
