MeCP2 Levels Regulate the 3D Structure of Heterochromatic Foci in Mouse Neurons
MeCP2 Levels Regulate the 3D Structure of Heterochromatic Foci in Mouse Neurons
复制标题
DOI：
10.1523/jneurosci.1281-19.2020
复制
发表时间：
2020-11-04
影响因子：
5.3
通讯作者：
Zoghbi, Huda Y.
中科院分区：
文献类型：
--
作者：
Ito-Ishida, Aya;Baker, Steven A.;Zoghbi, Huda Y.
甲基-CpG 结合蛋白 2 (MeCP2) 是一种对正常脑功能至关重要的核蛋白，MeCP2 的缺失和过度表达分别会导致严重的神经发育疾病、Rett 综合征 (RTT) 和 MECP2 增殖障碍。然而，异常MeCP2剂量导致神经元功能障碍的分子机制仍不清楚。由于 MeCP2 的表达几乎与核心组蛋白的表达相同，并且它与整个基因组中的 DNA 结合，因此 MeCP2 的一项可能功能是调节染色质的 3D 结构。在这里，为了检查 MeCP2 水平是否以及如何影响染色质结构，我们使用高分辨率共聚焦和电子显微镜检查了小鼠神经元的异染色质灶。使用RTT和MECP2三倍体综合征模型，我们发现异染色质结构受到MeCP2水平改变的显着影响。对表达 MeCP2-R270X 或 MeCP2G273X 的小鼠的分析表明，异染色质变化的程度与表型严重程度密切相关，这些小鼠的 AT-hook 2 结构域的上游和下游区域分别具有无义突变。出生后 MeCP2 水平的变化也引起异染色质结构的显着变化，这强调了成熟神经元中正确的 MeCP2 剂量的重要性。最后，对 MeCP2 过表达小鼠的功能分析表明，这些小鼠的行为和转录组变化与 MeCP2 水平显着相关，并且与异染色质变化同时发生。总而言之，我们的研究结果证明了 MeCP2 在调节神经元染色质 3D 结构中的重要作用，这可能是驱动 MeCP2 相关疾病发病机制的潜在机制。
Methyl-CpG binding protein 2 (MeCP2) is a nuclear protein critical for normal brain function, and both depletion and overexpression of MeCP2 lead to severe neurodevelopmental disease, Rett syndrome (RTT) and MECP2 multiplication disorder, respectively. However, the molecular mechanism by which abnormal MeCP2 dosage causes neuronal dysfunction remains unclear. As MeCP2 expression is nearly equivalent to that of core histones and because it binds DNA throughout the genome, one possible function of MeCP2 is to regulate the 3D structure of chromatin. Here, to examine whether and how MeCP2 levels impact chromatin structure, we used high-resolution confocal and electron microscopy and examined heterochromatic foci of neurons in mice. Using models of RTT and MECP2 triplication syndrome, we found that the heterochromatin structure was significantly affected by the alteration in MeCP2 levels. Analysis of mice expressing either MeCP2-R270X or MeCP2G273X, which have nonsense mutations in the upstream and downstream regions of the AT-hook 2 domain, respectively, showed that the magnitude of heterochromatin changes was tightly correlated with the phenotypic severity. Postnatal alteration in MeCP2 levels also induced significant changes in the heterochromatin structure, which underscored importance of correct MeCP2 dosage in mature neurons. Finally, functional analysis of MeCP2-overexpressing mice showed that the behavioral and transcriptomic alterations in these mice correlated significantly with the MeCP2 levels and occurred in parallel with the heterochromatin changes. Taken together, our findings demonstrate the essential role of MeCP2 in regulating the 3D structure of neuronal chromatin, which may serve as a potential mechanism that drives pathogenesis of MeCP2-related disorders.