Molecular Pathogenesis Studies of Rett Syndrome

Rett综合征的分子发病机制研究

• 批准号: 8236446
• 负责人: HUDA Y ZOGHBI
• 金额: $ 34.41万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-04 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236446
• 关键词: Affect; Alleles; Animal Model; Architecture; Autistic Disorder; Binding; Brain; Cerebellum; Chromatin; Chromatin Structure; Complex; CpG dinucleotide; DNA; Data; Disease; Down-Regulation; Encephalopathies; Enhancers; Equilibrium; Family; Female; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Genome; Grant; Histone Deacetylase; Histone H1; Histone H1(s); Histones; Homologous Gene; Hypothalamic structure; Immune Sera; Impaired cognition; Lead; Link; Maps; Mediating; Methyl-CpG-Binding Protein 2; Methylation; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; Neonatal; Neurons; Neurotransmitters; Noise; Nucleosomes; Partner in relationship; Pathogenesis; Patients; Pattern; Phenotype; Polycomb; Progress Reports; Proteins; Psychotic Disorders; Publishing; Repetitive Sequence; Research; Rett Syndrome; Role; SPT6 Protein; Syndrome; Testing; Tetracyclines; Therapeutic; Transcription Repressor/Corepressor; Transgenic Mice; Work; base; brain tissue; chromatin immunoprecipitation; chromatin remodeling; disease phenotype; early onset; effective therapy; genome-wide; histone acetyltransferase; in vivo; inhibitor/antagonist; insight; male; motor impairment; mouse model; mutant; neuropsychiatry; overexpression; preclinical study; promoter; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): Methyl-CpG-binding protein 2 (MeCP2) was first purified over twenty years ago and identified as a transcriptional repressor that binds to methylated CpG dinucleotides. Eleven years ago our lab discovered that mutations in the X-linked MECP2 gene cause Rett Syndrome (RTT, MIM312750). We now know that MECP2 mutations (as well as duplications or triplications of the wild-type gene) cause a variety of neuropsychiatric disorders, ranging from neonatal encephalopathy to autism, various kinds of cognitive and motor impairments, and early-onset psychosis in males and females. It also appears that MeCP2 is not a straightforward transcriptional repressor. Through work supported by the last renewal of this grant, we made the surprising discovery that MECP2 overexpression increases the expression levels of 80% of the hypothalamic genes it appears to regulate, whereas loss of MeCP2 results in decreased expression of the same genes. More puzzling still, chromatin immunoprecipitation (ChIP)-chip and ChIP-seq data as well as locus-specific ChIP data show that MeCP2 binds widely throughout the genome but that it is especially concentrated at specific promoters. How MeCP2 binding to promoter or non-promoter DNA increases neuronal gene expression is unclear. We hypothesize that MeCP2 modulates chromatin architecture but that it also has unique functions at select neuronal promoters. In our first aim, therefore, we will map the genome-wide occupancy of MeCP2 in the brain and compare the results with our existing expression data in MeCP2 mouse models to determine if there is a relationship between MeCP2 promoter occupancy and changes in gene expression. In our second aim, we will test the hypothesis that MeCP2 serves as an alternative linker histone, and determine whether there is an essential balance between MeCP2 and H1 levels in brain tissue, as well as elucidate the functional relationship between these two factors. In the third aim, we will examine MeCP2 interactions with the chromatin remodeling protein Ezh1 (an in vivo partner of MeCP2 we recently identified, whose spatiotemporal expression pattern parallels that of MeCP2); in both aims 2 and 3 we will test how these interactions might mediate MeCP2 phenotypes through the generation of new mouse models. Finally, our fourth aim extends our work suggesting that altering gene expression might mitigate RTT and MeCP2 duplication phenotypes. We will test therapies targeting chromatin status (HDAC and HAT inhibitors) in mouse models of RTT and MECP2 duplication syndrome. These four aims will settle several fundamental questions about MeCP2's roles in transcription, will yield important insights into chromatin alterations in neurons that cannot be approached without in vivo studies, and could yield promising candidate therapies. PUBLIC HEALTH RELEVANCE: Mutations in MECP2 cause Rett syndrome as well as a host of other neuropsychiatric disorders. Our recent progress has led to possible therapeutic approaches we will test in our well-characterized mouse models, while we also seek to answer fundamental questions about MeCP2's influence on neuronal gene transcription.

描述（由申请人提供）：二十年前首次纯化甲基-CPG结合蛋白2（MECP2），并被确定为与甲基化CPG CPG二核苷酸结合的转录阻遏物。十一年前，我们的实验室发现，X连锁MECP2基因的突变导致RETT综合征（RTT，MIM312750）。我们现在知道，MECP2突变（以及野生型基因的重复或三分之一）引起了多种神经精神疾病，从新生儿脑病到自闭症，到各种认知和运动障碍，以及男性和女性的早期精神病。似乎MECP2不是直接的转录阻遏物。通过该赠款的最后一次续签支持的工作，我们令人惊讶地发现，MECP2的过表达增加了下丘脑基因的80％的表达水平，而MECP2的丧失导致同一基因的表达降低。更令人困惑的是，染色质免疫沉淀（CHIP）-CHIP和CHIP-SEQ数据以及基因座特异性芯片数据表明，MECP2在整个基因组中都广泛结合，但特别集中在特定启动子上。 MECP2与启动子或非促启动子DNA的结合尚不清楚神经元基因表达。我们假设MECP2调节染色质架构，但在某些神经元启动子中也具有独特的功能。因此，在我们的第一个目标中，我们将绘制大脑中MECP2的全基因组占用率，并将结果与​​MECP2小鼠模型中的现有表达数据进行比较，以确定MECP2启动子占用率与基因表达的变化之间是否存在关系。在我们的第二个目标中，我们将检验以下假设：MECP2用作替代性接头组蛋白，并确定MECP2和H1水平之间是否在脑组织中存在基本平衡，并阐明了这两个因素之间的功能关系。在第三个目标中，我们将研究MECP2与染色质重塑蛋白EZH1（MECP2的体内伴侣我们最近鉴定出来的MECP2相互作用，其时空表达模式与MECP2的时空表达模式相似）；在两个目标2和3中，我们将测试这些相互作用如何通过新的鼠标模型来介导MECP2表型。最后，我们的第四个目标扩展了我们的工作，这表明改变基因表达可能会减轻RTT和MECP2重复表型。我们将在RTT和MECP2复制综合征的小鼠模型中测试靶向染色质状态（HDAC和HAT抑制剂）的疗法。这四个目标将解决有关MECP2在转录中角色的几个基本问​​题，将产生对神经元染色质改变的重要见解，而没有体内研究就无法处理，并且可以产生有希望的候选疗法。 公共卫生相关性：MECP2的突变导致RETT综合征以及许多其他神经精神疾病。我们最近的进步导致了可能的治疗方法，我们将在良好的小鼠模型中测试，同时我们也寻求回答有关MECP2对神经元基因转录影响的基本问题。