Identification and characterization of chromatin regulators of coordinated synaptic gene expression

协调突触基因表达的染色质调节因子的鉴定和表征

• 批准号: 10391155
• 负责人: Erica Nicole Larschan
• 金额: $ 42.93万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391155
• 关键词: ATAC-seq; Adult; Behavior; Binding; Brain; Candidate Disease Gene; Cell Nucleus; Cells; Chemical Synapse; Chromatin; Communities; Complex; DNA Binding; Data; Data Set; Development; Drosophila genus; Equilibrium; Event; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Letters; Logic; Modeling; Molecular; Multiomic Data; Nervous System Physiology; Nervous system structure; Neurobiology; Neuronal Differentiation; Neurons; Publishing; Regulation; Regulator Genes; Reporting; Resources; Role; Specific qualifier value; Synapses; System; Testing; Validation; Visual system structure; cofactor; in vivo; machine learning method; multiple omics; mutant; nervous system development; neural circuit; programs; promoter; single-cell RNA sequencing; stem cells; synaptogenesis; trait; transcription factor; transcriptome sequencing; transcriptomics

Project Summary/Abstract Nervous system function requires the integration of diverse neuronal subtypes into neural circuits that elicit thought and behavior. Despite the extensive diversity of neuronal subtypes, all neurons share key features, including chemical synapses. Current models indicate that shared neuronal genes, including pan-synaptic genes, are independently regulated by different combinations of transcription factors in distinct neuronal subtypes, whereas subtype-specific synaptic genes are regulated by specific transcription factors called terminal selectors. Our data demonstrate that pan-neuronal and subtype-specific synaptic genes are temporally coordinated during synaptogenesis. We have identified a candidate gene regulatory network (GRN) that includes two known pioneer factors, and propose a model in which positive and negative regulation of chromatin accessibility underlie the coordinated regulation of synaptic gene expression to promote synapse formation. In Aim 1, we propose genomic and in vivo functional validation to test the model that two of our candidate transcription factors, GA-rich motif binding factors CLAMP and GAGA factor, bind to the same promoters of synaptic genes to exert opposite effects on chromatin accessibility and transcription. In Aim 2, we propose a comprehensive and unbiased approach to identifying the GRNs underlying coordinated synaptic gene expression through single-nucleus RNA- and ATAC-Seq. Successful completion of these studies will advance our understanding of how the development of shared neuronal traits is coordinated with cell fate acquisition, and may inform neuronal reprogramming of stem cells.

项目总结/摘要 神经系统功能需要不同的神经元亚型整合到神经系统中。 引发思想和行为的电路。尽管神经元亚型的广泛多样性，所有 神经元具有共同的关键特征，包括化学突触。目前的模型表明， 神经元基因，包括泛突触基因，由不同的基因独立调控。 不同神经元亚型中转录因子的组合，而亚型特异性 突触基因由称为末端选择子的特定转录因子调节。我们的数据 表明泛神经元和亚型特异性突触基因在时间上是协调的 在突触形成过程中。我们已经确定了一个候选基因调控网络（GRN）， 包括两个已知的先驱因素，并提出了一个模型，其中积极和消极的 染色质可及性调节是突触基因协调调节的基础 表达以促进突触形成。在目标1中，我们提出了基因组和体内功能， 验证，以测试我们的两个候选转录因子，GA丰富的基序结合模型， CLAMP因子和GAGA因子与突触基因的相同启动子结合， 对染色质可及性和转录的相反影响。在目标2中，我们提出了一个 全面和公正的方法来识别协调突触的GRNs 通过单核RNA和ATAC-Seq.成功完成这些 这些研究将促进我们对共同神经元特征的发展是如何影响人类的理解。 与细胞命运获取协调，并且可以告知干细胞的神经元重编程。