Role of autism-associated chromatin remodeler Brg1 in neuronal development

自闭症相关染色质重塑蛋白 Brg1 在神经元发育中的作用

• 批准号: 8623709
• 负责人: Jiang Wu
• 金额: $ 23.85万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623709
• 关键词: ATP phosphohydrolase; Accounting; Autistic Disorder; Binding; Brain; Cell physiology; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complex; Confocal Microscopy; Data; Defect; Dendritic Spines; Development; Disease; Epigenetic Process; Equilibrium; Excitatory Synapse; Functional disorder; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Hippocampus (Brain); Imaging Device; Inhibitory Synapse; Label; Learning; Light; Link; Measures; Mediating; Memory; Molecular; Morphology; Mutation; Neurons; Overlapping Genes; Pathogenesis; Phenotype; Play; Protein Family; Proteins; Proteomics; Recruitment Activity; Regulation; Reporter; Reporting; Research; Role; Signal Transduction; Site; Slice; Symptoms; Synapses; Synaptic plasticity; Testing; Work; autism spectrum disorder; base; chromatin modification; chromatin remodeling; genome-wide; insight; molecular imaging; mutant; neurodevelopment; neuron development; novel; postsynaptic; presynaptic; public health relevance; research study; response; synaptogenesis; therapeutic target; transcription factor; transcriptome sequencing

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.

总结 自闭症谱系障碍（ASD）是一种由遗传和表观遗传因素调控的复杂疾病， 突触功能障碍作为一个中心缺陷。许多ASD相关基因直接编码蛋白质 在突触或突触基因的调节器中起作用。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一起起作用，以指导基因表达， 发展和环境信号。最近，ATP依赖的染色质重塑BAF 复合体与自闭症有关编码几个BAF亚基的基因突变，包括核心 ATP酶亚基Brg1导致具有自闭症症状的疾病。我之前的研究发现 哺乳动物神经元特异性BAF复合物，其在神经元发育中起重要作用。然而，在这方面， 其在突触形成和自闭症表型中的作用仍然未被探索。为了阐明BAF的功能， 神经元基因表达和突触发育，我们专门删除Brg1在发育中的神经元。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，在调节神经元凋亡中起关键作用。 ASD相关基因与突触可塑性MEF2C激活的报告基因表达显著受损 Brg1突变型神经元中。我们的蛋白质组学研究还确定了MEF2C作为神经元中的Brg1相互作用蛋白。 基于MEF2C在突触发育和ASD发病机制中的作用，我们推测Brg 1可能与突触发育和ASD发病有关。 通过促进MEF2C介导的活性依赖性基因表达来调节神经元突触发育。 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Brg 1在突触发育和可塑性中的功能。我们的研究将提供 重要的见解，了解表观遗传机制调节基因表达， ASD中的突触发生