Mechanisms of Genome Architecture Regulation in Motor Learning

这项研究的目的是阐明神经元细胞凋亡过程中基因组组织的机制。 活性，并确定这些机制在学习和记忆中的作用。我们最近发现 动物的感官体验控制着大脑中神经元基因组结构的重塑。 基因调控增强子和启动子之间的局部基因组相互作用的快速诱导驱动了基因表达。 上调活动依赖性基因表达以促进运动学习。然而，数百个基因 下调与体内神经元活动，这一发现已被观察到在多个脑区， 未知的机制和功能。这就提出了一个根本性的问题， 活动依赖性转录抑制以及这些大型遗传程序在运动中的功能是什么？ 学习在这项拨款申请中，我们将探讨潜在的分子机制和生物学功能， 基因阻遏控制中多尺度的3D基因组组织。 首先，我们将确定神经元活动是否可能触发序列特异性转录因子重塑 包括基因调节增强子和启动子之间的局部基因组结构。根据我们的发现， 我们将测试这一假设，即大脑富集的转录因子的调节触发了 增强子-启动子相互作用在神经元活性的存在下抑制基因转录。此外，委员会认为， 我们还将检验由这些转录因子维持的局部基因组结构发挥作用的假设， 在小鼠的运动学习中起着关键作用。这些实验将揭示分子机制， 动态调节大脑中的局部基因组结构。 第二，我们将确定是否重塑远程基因组相互作用，包括相互作用， 不同染色体之间的相互作用可能调节活性依赖的基因阻遏。根据我们初步的 研究结果，我们将测试假设1）在未刺激的神经元，基因形成染色体间的相互作用 与参与主动转录的特定核小体，以及2）与这些核小体的基因相互作用减弱 神经元活动期间的核体减弱基因表达。此外，我们还将检验假设 这些在成年神经元中发现的核体在运动神经元的获得或表达中起着特殊的作用， 老鼠的记忆这些实验将阐明脑富集核体在转录中的作用 和长期记忆。 这项拟议中的研究将有可能促进我们对基因组组织原则的理解， 局部和远程基因组尺度在控制神经回路细化和适应性变化， 生物行为因为基因组结构蛋白和突触蛋白的突变与 我们的研究还将提供一个关于感官体验如何影响人类认知障碍的综合观点。 协调从细胞核到突触的过程，以确保大脑的可塑性和健康。

The goals of the proposed research are to elucidate mechanisms of genome organization during neuronal activity in vivo and determine the roles of these mechanisms in learning and memory. We recently discovered that the sensory experience of animals controls the remodeling of neuronal genome architecture in the brain. The rapid induction of local genomic interactions between gene regulatory enhancers and promoters drives the upregulation of activity-dependent gene expression to promote motor learning. However, hundreds of genes are downregulated with neuronal activity in vivo, a finding that has been observed in multiple brain areas with unknown mechanisms and functions. This raises fundamental questions of what are the mechanisms that control activity-dependent transcriptional repression and what are the functions of these large genetic programs in motor learning. In this grant proposal, we will interrogate potential molecular mechanisms and biological functions of 3D genome organization at multiple scales in the control of gene repression. First, we will determine if neuronal activity might trigger sequence-specific transcription factors to remodel local genome architecture including between gene regulatory enhancers and promoters. Based on our findings, we will test the hypothesis that regulation of brain-enriched transcription factors triggers the breaking of enhancer-promoter interactions in the presence of neuronal activity to repress gene transcription. Furthermore, we will also test the hypothesis that local genome architecture maintained by these transcription factors play a critical role for motor learning in mice. These experiments will shed light on molecular mechanisms that dynamically regulate local genome architecture in the brain. Second, we will determine if remodeling of long-range genomic interactions including interactions between different chromosomes might regulate activity-dependent gene repression. Based on our preliminary findings, we will test the hypotheses that 1) in unstimulated neurons, genes form inter-chromosomal interactions with specific nuclear bodies involved in active transcription and 2) weakening of gene interactions with these nuclear bodies during neuronal activity attenuates gene expression. In addition, we will also test the hypothesis that these nuclear bodies found in adult neurons play specific roles in the acquisition or expression of motor memories in mice. These experiments will illuminate the roles of brain-enriched nuclear bodies in transcription and long-term memory. The proposed research will potentially advance our understanding of genome organization principles at both local and long-range genomic scales in the control of neural circuit refinement and adaptive changes in organismal behavior. Because mutations of genome architectural proteins and synaptic proteins are linked to disorders of cognition in humans, our research will also provide an integrated view on how sensory experiences orchestrate processes from the cell nucleus to the synapse to ensure a plastic and healthy brain.