The Role of MeCP2 in Rett Syndrome

MeCP2 在 Rett 综合征中的作用

• 批准号: 8800422
• 负责人: Janine M LaSalle
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8800422
• 关键词: Address; Affinity; Age; Amino Acids; Animals; Antibodies; Anxiety; Astrocytes; Autistic Disorder; Behavior; Behavioral; Binding; Binding Proteins; Binding Sites; Biochemical; Brain; Breeding; Calculi; Cells; Cessation of life; Chromatin; Chromatin Structure; Collaborations; DNA; DNA Methylation; Development; Disease; Embryo; Epigenetic Process; Epilepsy; Exhibits; Feeding behaviors; Female; Fibroblasts; Future; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Grooming; Health; Heterogeneity; High Prevalence; Human; In Vitro; Investigation; Knowledge; Lamin B1; Link; Metabolic; Metabolism; Methyl-CpG-Binding Protein 2; Methylation; Molecular; Monitor; Motor Skills; Movement; Mus; Mutation; N-terminal; Neurodevelopmental Disorder; Neurologic; Neurons; Nuclear Protein; Pathway interactions; Phenotype; Phosphorylation; Phosphorylation Site; Population; Post-Translational Protein Processing; Protein Isoforms; Proteins; RNA Splicing; Reading; Recombinant Proteins; Research; Rett Syndrome; Role; Schizophrenia; Signal Transduction; Sorting - Cell Movement; Specificity; Structure; Symptoms; System; Testing; Time; Transcriptional Activation; Transgenic Mice; Wild Type Mouse; base; behavior test; chromatin immunoprecipitation; cofactor; design; epigenomics; gene repression; genome wide methylation; genome-wide; in vivo; interdisciplinary approach; male; mammalian genome; methylome; mouse model; mutant; mutant mouse model; nerve stem cell; neurodevelopment; neuron development; novel; postnatal; prenatal; social

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.

描述（由申请人提供）：Rett综合征是由基因MECP 2突变引起的，MECP 2编码一种与整个哺乳动物基因组中的甲基化DNA结合的表观遗传因子。MeCP2具有多个描述的功能结构域，但分子的大部分是固有的无序蛋白，这意味着它不编码确定的二级结构。已经描述了MeCP2的至少两种可变剪接同种型和多个磷酸化位点。此外，已经观察到MeCP2的多种相互作用蛋白，这些蛋白开始解释MeCP2如何具有如此多样化的功能，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性和成熟，但MeCP2也是一种丰富的核蛋白，在神经元中结合并作用于染色质动力学。MeCP2的分子复杂性似乎与作为主表观遗传调节剂的作用一致，所述主表观遗传调节剂在发育和成熟的哺乳动物大脑中调节并受多个信号转导和表观遗传途径调节。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位点，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。本申请集中于最丰富但研究不足的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，包括出生后神经系统症状的延迟发作，社交能力降低，高架十字迷宫的缺陷和早期致死性。总体目标是了解MeC2e1与MeCP2e2在出生前和出生后大脑发育中的功能及其与行为的相关性的结构和生化基础。目的1研究MeCP 2e1和MeCP 2e2在体内外结构和功能上的差异。目的2将通过联合基因组方法研究MeCP 2e1在识别发育神经元动态DNA甲基化组中的发育作用。目的3将探讨MeCP 2e1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Rett综合征和其他更常见的神经发育障碍（包括自闭症）相关的神经发育表观遗传途径具有重要意义。