Role of autism-associated chromatin remodeler Brg1 in neuronal development

摘要 自闭症谱系障碍(ASD)是一种受遗传和表观遗传因素调控的复杂疾病，具有 作为中枢缺陷的突触功能障碍。许多ASD相关基因直接编码这两种蛋白中的任何一种 在突触中起作用或调节突触基因。通过调节染色质结构和修饰， 表观遗传调节因子与转录因子共同作用，指导基因表达 发展和环境信号。最近，依赖于ATP的染色质重塑BAF 复合体已经与ASD联系在一起。编码包括核心在内的几个BAF亚基的基因突变 ATPase亚单位BRG1会导致具有自闭症症状的疾病。我之前的研究发现了一种 哺乳动物神经元特异的BAF复合体，在神经元发育中发挥重要作用。然而， 它在突触形成和自闭症表型中的作用尚不清楚。阐明曝气生物滤池在体内的作用 在神经元基因表达和突触发育的研究中，我们特异性地删除了发育中神经元中的BRG1。BRG1 缺失导致一组特定的神经元基因的活性依赖性表达受损，这些基因与 MEF2目标。MEF2C是一种神经元活性反应性转录因子，在调节 ASD相关基因与突触可塑性。MEF2C激活的报告表达显著受损 在BRG1突变神经元中。我们的蛋白质组学研究也发现MEF2C是神经元中的一种BRG1相互作用蛋白。 根据MEF2C在突触发育和ASD发病机制中的作用，我们假设BRG1 通过促进MEF2C介导的活性依赖基因的表达来调节神经元突触的发育。 在该提案中，我们将使用分子、细胞和基因组方法的组合来测试 假设并确定BRG1在突触发育和可塑性中的功能。我们的研究将提供 对理解表观遗传调控基因表达机制的重要启示 自闭症中的突触发生。

Summary 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.