Mechanisms of Genome Organization in Brain Development and Behavior

项目摘要 这项拟议研究的长期目标是阐明三维基因组的机制。 在大脑中控制神经元连接的结构。最近发现，生理性的 包括感觉体验或发育信号在内的刺激在体内重塑神经元基因组结构。 令人惊讶的是，研究发现，在发育过程中，远距离基因组相互作用大量增加 小鼠的小脑。这些在基因之间形成的长距离相互作用的发现对 神经元分化揭示了新的核机制，基因组结构可能通过这些机制在 大脑的连线。这些发现提出了关于血管紧张素转换酶的机制和生物学功能的根本问题。 大脑中的这些相互作用，这将在这项拨款中解决。第一，组织原则 大脑中的远程基因组相互作用将被阐明。根据体内的研究结果， 假设远距离基因组相互作用是由特定的表观遗传和 将对转录特征进行测试。此外，这项研究还将检验这一假设 长距离相互作用的锚聚集成更高顺序的亚核结构，包括 核斑点或介体凝聚体，其功能是转录活性中心。第二， Projcet将定义在开发过程中形成远程交互的机制。《BAF》 染色质重塑复合体改变基因组环境以激活或抑制转录，并 在小鼠和人类的大脑发育中所需的，以及它的失调导致人类 神经发育障碍，包括棺材-西里斯综合征和自闭症。根据我们的初步调查 发现，假设BAF复合体暂时抑制长距离基因组的形成 将测试发育中的大脑未成熟神经元之间的相互作用。在早期开发之后， 对远距离相互作用的抑制可能通过招募特定的组 驱动终末神经元分化的转录因子。这个项目将检验这样的假设： 通过DNA基序分析确定的转录调节因子，促进了长距离的形成 基因组相互作用。最后，本研究还将检验长距离形成的假说 基因组相互作用是体内神经元成熟所必需的，包括使适当的 与突触前和突触后伙伴的联系。这项拟议的研究具有重大意义，因为它将 促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潜在行为的神经回路的组装。

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.