Role of Brg1 in Activity-Induced Neuronal Gene Expression and Synaptic Plasticity

Brg1 在活动诱导的神经元基因表达和突触可塑性中的作用

• 批准号: 9276806
• 负责人: Jiang Wu
• 金额: $ 35.24万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276806
• 关键词: ATP phosphohydrolase; Autistic Disorder; Binding; Biochemical; Bromodomain; Calcium; Candidate Disease Gene; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complex; Data; Defect; Dendritic Spines; Development; Disease; Enhancers; Epigenetic Process; Functional disorder; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Goals; Growth; Light; Link; Mediating; Modification; Morphology; Mutation; Neurologic; Neurons; Pathogenesis; Pharmacology; Phosphorylation; Phosphotransferases; Physiological; Play; Post-Translational Protein Processing; Process; Proteins; Proteomics; Recruitment Activity; Regulation; Role; SMARCA4 gene; Signal Pathway; Signal Transduction; Specificity; Stimulus; Symptoms; Synapses; Synaptic plasticity; System; autism spectrum disorder; base; chromatin modification; chromatin remodeling; epigenetic regulation; experimental study; genetic approach; histone modification; insight; nervous system disorder; neuron development; novel; novel therapeutic intervention; optogenetics; response; synaptogenesis; transcription factor

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. 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.

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Brg 1导致具有自闭症症状的疾病。最近的大规模基因组研究预测， BAF核心亚基Brg 1（也称为SmarcA 4）是ASD基因网络的关键节点之一。我 以前的研究已经确定了哺乳动物神经元特异性BAF（nBAF）复合物，它在神经元的功能中起着重要的作用。 在活性诱导的树突生长中的作用，表明Ca 2+信号诱导的染色质调节基因 表情我实验室最近的研究表明，Brg 1是突触发育所必需的， 成熟我们发现Brg 1是ASD介导的树突棘/突触消除所必需的， 相关转录因子MEF 2C和Brg 1调节活性诱导的特异性 与MEF 2的靶标显著重叠的基因的子集。我们的分析表明，Brg 1相互作用 与MEF 2和MEF 2是需要Brg 1募集到靶基因响应神经元激活。 我们的基因组和蛋白质组数据进一步表明，Brg 1被神经元活动激活，并被招募到 通过MEF 2和活性组蛋白修饰增强子。我们假设Brg 1经历活动- 依赖性修饰改变并与MEF 2和动态表观遗传复合物协调， 调节靶基因激活和突触可塑性。在该提案中，我们将确定（1）Brg 1如何 通过转录因子和表观遗传标记对神经元激活的反应来招募，（2）Brg 1是如何被激活的？ Brg 1是如何通过神经元活动激活并调节靶基因转录的;（3）Brg 1如何调节神经元活动 基因表达和突触可塑性诱导的生理水平的活动。我们的研究将提供 对正常神经元发育的表观遗传调节和对神经系统发育的影响的机制见解 ASD等疾病。