Mechanisms of Genome Architecture Regulation in Motor Learning

这项拟议的研究的目标是阐明神经细胞基因组组织的机制。 并确定这些机制在学习和记忆中的作用。我们最近发现 动物的感觉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局部基因组相互作用的快速诱导推动了 上调依赖活动的基因表达以促进运动学习。然而，数以百计的基因是 体内神经元活性下调，这一发现已在多个脑区观察到 未知的机制和功能。这就提出了一个根本的问题，那就是控制 依赖活性的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。在这项拨款提案中，我们将询问潜在的分子机制和生物学功能。 控制基因抑制的多尺度三维基因组组织。 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 包括基因调控增强子和启动子之间的局部基因组结构。根据我们的发现， 我们将检验这样一种假设，即对大脑丰富的转录因子的调节触发了对 在神经元活性存在的情况下增强启动子-启动子的相互作用以抑制基因转录。此外， 我们还将测试由这些转录因子维持的局部基因组结构发挥作用的假设 对小鼠运动学习的关键作用。这些实验将阐明 动态调节大脑中的局部基因组结构。 第二，我们将确定包括相互作用在内的远程基因组相互作用的重塑 不同染色体之间的差异可能调节依赖活性的基因抑制。根据我们的初步调查 发现，我们将检验以下假设：1)在未经刺激的神经元中，基因形成染色体间的相互作用 具有参与活跃转录的特定核体，以及2)减弱与这些基因的相互作用 神经元活动时的核体会减弱基因的表达。此外，我们还将检验这一假设 在成年神经元中发现的这些核体在运动的获得或表达中起着特定的作用 老鼠的记忆。这些实验将阐明富含大脑的核体在转录中的作用。 和长期记忆。 拟议的研究可能会促进我们对基因组组织原理的理解 局部和远程基因组尺度在控制神经回路精细化和适应性变化中的作用 有机体的行为。因为基因组结构蛋白和突触蛋白的突变与 人类的认知障碍，我们的研究还将提供一个关于感觉体验如何 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.