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

虽然表观遗传修饰通常是通过转录因子对其同源识别序列的识别来启动的，但它是染色质结构变化的传播，是变化的效应器。异染色质蛋白1(HP1)成员动态地塑造这种变化，并被认为带来可遗传的(细胞到细胞)基因表达能力的变化，这种变化可以涵盖大范围的基因组。除了沉默结构基因外，HP1蛋白对沉默重复序列可能更重要，包括转座元件(TES)和内源性逆转录病毒(ERV)，它们的去抑制与多种神经精神和神经退行性病变有关。在这里，我们概述了我们的计划，从具体的分子和细胞角度了解哺乳动物HP1蛋白促进大脑皮层正常发育和功能的机制(S)。我们的初步工作已经在HP1突变体中发现了几种有趣的表型，这些表型可能是加速衰老的模型。在新皮质中缺乏HP1beta和HP1Gamma的动物表现出空间学习障碍，并表现出齿状回和大脑皮层的畸形。同时，这些动物在皮质，特别是海马区的有丝分裂后神经元中表现出内源性逆转录病毒的去抑制，这意味着HP1蛋白是逆转录病毒在神经元中沉默所必需的。为了理解这些现象，我们提出了HP1单突变体和双突变体的全谱特征。这包括结构特征、网络和突触分析，此外还包括反转录转座子活性的确定，以及这可能如何导致RNAseq测量的嵌合和异常基因转录。随着表观基因组年龄相关变化的共识出现，一个一致的观察是异染色质的丢失先于重复元件的表达1。我们提出的对海马区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。

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.