Mechanisms of Genome Organization in Brain Development and Behavior

大脑发育和行为中的基因组组织机制

• 批准号: 10684730
• 负责人: Tomoko Yamada
• 金额: $ 47.46万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684730
• 关键词: 3-Dimensional; Address; Architecture; B-Lymphocytes; Behavior; Binding; Biological; Biological Process; Brain; Cell Nucleus; Cerebellum; Chromatin; Chromatin Remodeling Factor; Chromosomes; Coffin-Siris Syndrome; Cognition Disorders; Complex; DNA; DNA Sequence Alteration; Data; Development; Enhancers; Ensure; Environment; Enzymes; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Goals; Grant; Homeobox; Human; Impairment; LIM Domain; Link; Locales; Mediator; Molecular; Morphogenesis; Mus; Mutation; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Nuclear; Nuclear Proteins; Pattern; Physical condensation; Physiological; Play; Proteins; RNA Processing; Reporting; Research; Role; Sensory; Shapes; Signal Transduction; Stimulus; Structure; Synapses; Testing; autism spectrum disorder; base; cancer cell; cell type; cofactor; embryonic stem cell; experience; gene repression; in vivo; insight; neural circuit; neural patterning; novel; olfactory sensory neurons; postsynaptic; presynaptic; recruit; transcription factor

Project Summary The long-term goals of the proposed research are to elucidate mechanisms of three-dimensional genome architecture in the control of neuronal connectivity in the brain. It has recently been found that physiological stimuli including sensory experience or developmental signals remodel neuronal genome architecture in vivo. Strikingly, it's found that long-distance genome interactions massively increase in the developing cerebellum in mice. The discovery of these long-distance interactions formed between genes critical for neuronal differentiation unveils novel nuclear mechanisms by which genome architecture may play a role in the wiring of the brain. These findings raise fundamental questions on the mechanisms and biological functions of these interactions in the brain, which will be addressed in this grant. First, the organizing principles of long-distance genome interactions in the brain will be elucidated. Based on the in vivo findings, the hypothesis that long-distance genomic interactions are organized by specific epigenetic and transcriptional features will be tested. In addition, the study will also test the hypothesis that anchors of long-distance interactions assemble into higher-ordered subnuclear structures including nuclear speckles or Mediator condensates, which function as transcriptionally active hubs. Second, the projcet will define mechanisms by which long-distance interactions are formed in development. The BAF chromatin remodeling complex alters the genome environment to activate or repress transcription and is required for brain development in mice and humans, and its dysregulation results in human neurodevelopmental disorders, including Coffin–Siris syndrome and autism. Based on our preliminary findings, the hypothesis that the BAF complex transiently inhibits formation of long-distance genome interactions in immature neurons of the developing brain will be tested. Following early development, the inhibition of the long-distance interactions might be relieved by the recruitment of specific sets of transcription factors that drive terminal neuron differentiation. This project will test the hypothesis that these transcription regulators, identified using DNA motif analyses, promote the formation of the long-distance genome interactions. Finally, this study will also test the hypothesis that the formation of long-distance genome interactions is necessary for the maturation of neurons in vivo, including making proper connections with their pre- and post-synaptic partners. The proposed research is significant as it will advance our understanding of the mechanisms regulating genome architecture to control neuronal differentiation in mammalian brain. Furthermore, these studies will provide an integrated view on how genome folding in the nucleus orchestrates the assembly of neural circuits underlying behavior.

项目摘要 该研究的长期目标是阐明三维基因组的机制 控制大脑中神经元连接的结构。最近发现， 包括感觉经验或发育信号的刺激在体内重塑神经元基因组结构。 令人惊讶的是，发现长距离基因组相互作用在发育中大量增加， 小鼠小脑。这些长距离相互作用的发现形成于基因之间， 神经元分化揭示了新的核机制，基因组结构可能在神经元分化中发挥作用。 大脑的线路这些发现提出了有关的机制和生物学功能的基本问题， 大脑中的这些相互作用，这将在本基金中得到解决。第一，组织原则 大脑中的长距离基因组相互作用将得到阐明。根据体内研究结果， 假设长距离基因组相互作用是由特定的表观遗传和 将测试转录特征。此外，该研究还将检验假设， 长距离相互作用的锚组装成更高层次的亚核结构， 核斑点或介体凝聚物，其作为转录活性枢纽发挥作用。二是 项目将确定在发展中形成远距离互动的机制。生物曝气滤池 染色质重塑复合物改变基因组环境以激活或抑制转录， 在小鼠和人类的大脑发育所需的，其失调导致人类 神经发育障碍，包括Coffin-Siris综合征和自闭症。根据我们初步的 研究结果，假设BAF复合物瞬时抑制长距离基因组的形成， 将测试发育中的大脑的未成熟神经元中的相互作用。经过早期的发展， 长距离相互作用的抑制可能会通过招募特定的 转录因子驱动终末神经元分化。这个项目将测试假设，这些 使用DNA基序分析鉴定的转录调节因子促进长距离转录因子的形成， 基因组相互作用最后，本研究还将检验长距离形成的假说 基因组相互作用对于体内神经元的成熟是必要的，包括使适当的 与他们的突触前和突触后伙伴的联系。拟议的研究是重要的，因为它将 推进我们对调控基因组结构的机制的理解， 哺乳动物大脑中的神经元分化。此外，这些研究将提供一个综合的观点， 关于细胞核中的基因组折叠如何协调行为背后的神经回路的组装。