HP1-mediated Genome Stability in Normal Brain Development, Structure & Function

HP1介导的正常大脑发育、结构中的基因组稳定性

• 批准号: 410579311
• 负责人: Professor Dr. Victor Tarabykin
• 金额: --
• 依托单位: Institut für Zell- und Neurobiologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/410579311?language=en
• 关键词: HP1; mediated; Genome; Stability; Normal

While epigenetic modifications are typically initiated through recognition by a transcription factor to its cognate recognition sequence, it is the propagation of structural changes in chromatin which is the effector of change. Heterochromatin Protein 1 (HP1) members dynamically sculpt this change to and are thought to bring about heritable (cell-to-cell) changes in gene expressibility that can encompass large stretches of the genome. Aside from silencing structural genes, HP1 proteins are potentially more important for silencing repeats, including Transposable Elements (TEs) and Endogenous Retroviruses (ERVs), whose de-repression is associated with a variety of neuropsychiatric and neurodegenerative pathologies. Here we outline our plans to understand, in concrete molecular and cellular terms, the mechanism(s) by which mammalian HP1 proteins contribute to the normal development and function of the cerebral cortex. Our preliminary work has uncovered several interesting phenotypes in HP1 mutants that may model accelerated aging. Animals deficient for HP1beta and HP1gamma in the neocortex show deficits in spatial learning and display malformations of the dentate gyrus and cerebral cortex. Simultaneously, these animals display derepression of endogenous retroviruses in post-mitotic neurons of the cortex and especially hippocampus, implicating HP1 proteins as essential for retroviral silencing in neurons. To understand these phenomena we propose a full spectrum characterization of HP1 single and double mutants. This involves structural characterization, network and synapse analysis, in addition to a determination of retrotransposon activity and how this may lead to chimeric and aberrant gene transcription as measured by RNAseq. As a consensus of age-related changes to the epigenome emerges, a consistent observation is that loss of heterochromatin precedes the expression of repetitive elements1. Our proposed study of HP1–deficient neurons in the hippocampus aims to provide valuable insights into both the molecular underpinnings and the behavioral consequences of precocious epigenome dysregulation.

虽然表观遗传修饰通常通过转录因子对其同源识别序列的识别来启动，但它是染色质中结构变化的传播，染色质是变化的效应物。异染色质蛋白1（HP1）成员动态地塑造这种变化，并被认为会带来基因表达的可遗传（细胞到细胞）变化，这些变化可以涵盖基因组的大部分。除了沉默结构基因外，HP1蛋白对沉默重复序列（包括转座因子（TE）和内源性逆转录病毒（ERV））可能更重要，其去抑制与各种神经精神和神经退行性病变相关。在这里，我们概述了我们的计划，以了解，在具体的分子和细胞方面，哺乳动物HP1蛋白有助于大脑皮层的正常发育和功能的机制。 我们的初步工作已经发现了几个有趣的表型HP1突变体，可能模型加速老化。 新皮层中缺乏HP1 β和HP1 γ的动物表现出空间学习的缺陷，并显示齿状回和大脑皮层的畸形。同时，这些动物显示内源性逆转录病毒在有丝分裂后的皮质神经元，特别是海马，暗示HP1蛋白质作为必要的逆转录病毒沉默的神经元中的去抑制。 为了理解这些现象，我们提出了一个完整的光谱表征的HP1单，双突变体。这涉及结构表征，网络和突触分析，以及确定逆转录转座子活性以及如何通过RNAseq测量导致嵌合和异常基因转录。 随着年龄相关的表观基因组变化的共识出现，一致的观察是异染色质的丢失先于重复元件的表达1。 我们提出的海马中HP1缺陷神经元的研究旨在为早熟表观基因组失调的分子基础和行为后果提供有价值的见解。