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. My previous studies have identified a mammalian neuron specific BAF complex, which plays an essential role in neuronal development. However, its roles in synapse formation and autistic phenotypes remain unexplored. To elucidate BAF function in neuronal gene expression and synapse development, we specifically deleted Brg1 in developing neurons. Brg1 deletion resulted in impaired activity-dependent expression of a specific set of neuronal genes that overlap with MEF2 targets. MEF2C is a neuronal activity-responsive transcription factor that plays a key role in regulating ASD-associated genes and synapse plasticity. MEF2C-activated reporter expression was significantly impaired in Brg1-mutant neurons. Our proteomic studies also identified MEF2C as a Brg1-interacting protein in neurons. Based on the roles of MEF2C in synapse development and ASD pathogenesis, we hypothesize that Brg1 regulates neuronal synapse development by facilitating MEF2C-mediated activity-dependent gene expression. In the proposal, we will use a combination of molecular, cellular and genomic approaches to test the hypothesis and determine the function of Brg1 in synapse development and plasticity. Our studies will provide significant insights to the understanding of epigenetic mechanisms regulating gene expression in synaptogenesis in ASDs.
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 development. Our studies will provide novel insights into the epigenetic regulation of ASD-associated genes during synaptogenesis and will identify potential therapeutic targets for ASDs.
|Shi, Xuanming; Zhang, Zilai; Zhan, Xiaoming et al. (2014) An epigenetic switch induced by Shh signalling regulates gene activation during development and medulloblastoma growth. Nat Commun 5:5425|