The Role of MeCP2 in Rett Syndrome

描述(申请人提供)：Rett综合征是由MECP2基因突变引起的，MECP2编码一种表观遗传因子，该因子与整个哺乳动物基因组中的甲基化DNA结合。MeCP2有多个已描述的功能结构域，但该分子的大部分是一种天生无序的蛋白质，这意味着它不编码定义的二级结构。至少已描述了MeCP2的两种选择性剪接异构体和多个磷酸化位点。此外，已观察到MeCP2的多种相互作用蛋白，开始解释MeCP2可能具有如此多样化的一系列功能，包括全局染色质结构、转录抑制和转录激活。MeCP2的多个基因靶点已经出现，并有助于解释MeCP2如何调节神经元的活动和成熟，但MeCP2也是一种丰富的核蛋白，它结合并作用于神经元中的染色质动力学。在发育和成熟的哺乳动物大脑中，MeCP2的分子复杂性似乎与其作为一个主要的表观遗传调节因子的作用是一致的，该表观遗传调控因子既调节并受多种信号转导和表观遗传途径的调节。因此，了解MeCP2的翻译后修饰、异构体和不同的相互作用伙伴以及它们在全基因组范围内的结合部位对于了解其功能及其与RTT和相关神经发育障碍的相关性至关重要。该应用侧重于迄今未被研究的最丰富的MeCP2亚型，MeCP2e1。初步结果表明，选择性缺乏MeCP2e1的小鼠表现出与其他Rett小鼠模型相同的几个特征，包括神经症状出生后延迟出现，社交能力降低，在高架+迷宫中缺乏，以及早期死亡。总体目标是了解MeC2e1和MeCP2e2在出生前和出生后大脑发育中的结构和生化基础，以及它们与行为的相关性。目的1研究MeCP2e1和MeCP2e2在体内外结构和功能上的差异。目的2将研究MeCP2e1在通过联合基因组方法识别发育中神经元的动态DNA甲基组中的发育作用。目的3将研究MeCP2e1缺乏对社会、行为和代谢的影响。这些研究的结果有望对理解与Rett综合征和包括自闭症在内的其他更常见的神经发育障碍相关的神经发育表观遗传途径具有重要意义。

DESCRIPTION (provided by applicant): Rett syndrome is caused by mutation in the gene MECP2, encoding an epigenetic factor that binds to methylated DNA throughout the mammalian genome. MeCP2 had multiple described functional domains, but the majority of the molecule is an inherently disordered protein, meaning that is does not encode a defined secondary structure. At least two alternatively spliced isoforms and multiple phosphorylation sites of MeCP2 have been described. In addition, multiple interacting proteins of MeCP2 have been observed that are beginning to explain how MeCP2 may have such a diverse array of functions, including global chromatin structures, transcriptional repression, and transcriptional activation. Multiple gene targets of MeCP2 have emerged and help to explain how MeCP2 modulates neuronal activity and maturation, but MeCP2 is also an abundant nuclear protein that binds and acts globally on chromatin dynamics in neurons. The molecular complexities of MeCP2 appear to be consistent with a role as a master epigenetic regulator that both regulates and is regulated by multiple signal transduction and epigenetic pathways in the developing and mature mammalian brain. Therefore, understanding the post-translational modifications, isoforms and different interacting partners of MeCP2 as well as their binding sites genome-wide are expected to be critical for understanding its functions and their relevance to RTT and related neurodevelopmental disorders. This application focuses on the most abundant yet understudied MeCP2 isoform, MeCP2e1. Preliminary results demonstrate that mice selectively deficient in MeCP2e1 exhibit several features common to other Rett mouse models, including a delayed postnatal onset of neurological symptoms, reduced sociability, deficiencies in the elevated plus maze, and early lethality. The overall objective is to understand the structural and biochemical bases of MeC2e1 versus MeCP2e2 functions in pre- and postnatal brain development and their relevance to behavior. Aim 1 will investigate the structural and functional differences between MeCP2e1 and MeCP2e2 in vitro and in vivo. Aim 2 will investigate developmental roles for MeCP2e1 in recognizing the dynamic DNA methylome of developing neurons through combined genomic approaches. Aim 3 will investigate the social, behavioral, and metabolic effects of MeCP2e1 deficiency. The results of these studies are expected to be significant for understanding neurodevelopmental epigenetic pathways relevant for Rett syndrome and other more common neurodevelopmental disorders, including autism.