Neuronal Activity-Dependent Regulation of MeCP2

MeCP2 的神经元活动依赖性调节

基本信息

批准号：
9147483
负责人：
MICHAEL ELDON GREENBERG
金额：
$ 60.63万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-03-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9147483
关键词：
Address Affinity Amino Acids Animals Autistic Disorder Automobile Driving Binding Binding Proteins Biochemical Biological Assay Birds Brain Chromatin Complex Cytosine DNA DNA Methylation Defect Disease Down-Regulation Etiology Functional disorder Funding Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genome Grant Histone Deacetylase Histones Human Impaired cognition In Vitro Individual Laboratories Lead Learning Disabilities Length Link Mediating Mental Retardation Methods Methyl-CpG-Binding Protein 2 Methylation Modeling Molecular Mus Mutate Mutation Nervous system structure Neuraxis Neurodevelopmental Disorder Neurons Pathology Phenocopy Phenotype Phosphorylation Physiology Process Proteins Recruitment Activity Regulation Regulator Genes Rett Syndrome Role Sensory Severities Site Synapses Testing Topoisomerase Up-Regulation Woman autism spectrum disorder base cell type density experience gene function gene repression genome-wide girls in vivo insight loss of function mutation nervous system disorder neurodevelopment overexpression postnatal protein function public health relevance research study response sensory stimulus therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Mutations in MeCP2, a methyl-CG-binding protein that functions as a regulator of gene expression, are a major cause of Rett syndrome (RTT), an X-linked progressive neurological disorder associated with profound cognitive impairment in girls and women. MECP2 mutations also cause an array of other neurological disorders, including nonsyndromic mental retardation, learning disability, and autism. While the selective inactivation of MeCP2 in neurons has been suggested to be sufficient to confer a Rett-like phenotype in mice, the specific mechanisms by which the loss of MeCP2 function in postmitotic neurons gives rise to RTT pathology remain enigmatic. In preliminary studies we have discovered a subtle, yet consistent genome-wide length-dependent increase in the expression of long genes (>100 kb) in MeCP2-deficient neurons that correlates with phenotypic onset and severity in a variety of RTT models. These MeCP2-regulated long genes encode factors that modulate neuronal physiology, including a number of loci implicated in autism spectrum disorders. Remarkably, the long genes that are misregulated in RTT have a high density of non-CG DNA methylation (mCA) throughout their transcribed regions. Taken together with recent evidence that MeCP2 binds mCA with high affinity, our findings suggest that MeCP2 tempers the expression of long genes in the developing nervous system by binding mCA within their transcribed regions. Moreover, these results suggest that global disruption of the expression of long genes and/or the fidelity of transcription may underlie significant aspects of RTT pathology. To investigate these possibilities and to gain further insight into MeCP2 function in both neural development and RTT etiology, we propose (1) to characterize how non-CG DNA methylation contributes to MeCP2 function, and (2) to investigate the role of neuronal length-dependent gene misregulation in RTT pathophysiology. It is our hope that the proposed experiments will provide a better understanding of MeCP2 function, give insight into RTT etiology, and ultimately provide new opportunities for the development of therapeutic strategies to alleviate RTT pathology.

描述（由适用提供）：MECP2中的突变是一种作为基因表达调节剂的甲基-CG结合蛋白，是RETT综合征（RTT）的主要原因，RETT综合征（RTT）是与女孩和女性严重认知障碍相关的X连锁性渐进性神经系统疾病。 MECP2突变还引起了其他一系列其他神经系统疾病，包括非同步精神降低，学习障碍和自闭症。尽管已经认为MECP2在神经元中的选择性失活足以赋予小鼠中的RETT样表型，但MECP2在症状后神经元中的丧失引起RTT病理学的特定机制仍然神秘。在初步研究中，我们发现了MECP2缺乏性神经元中长基因（> 100 kb）表达的微妙但全基因组的长度依赖性增加，这与各种RTT模型中的表型发作和严重程度相关。这些由MECP2调节的长基因编码调节神经元生理的因子，包括与自闭症谱系障碍有关的许多基因座。值得注意的是，在RTT中被误导的长基因在其转录的区域中具有高密度的非CG DNA甲基化（MCA）。与最近证明MECP2结合MCA具有高亲和力的证据，我们的发现表明，MECP2温度通过在其转录区域内结合MCA，在发育中的神经系统中长基因的表达。此外，这些结果表明，长基因表达和/或转录的保真度的全球破坏可能是RTT病理学的重要方面。为了研究这些可能性并进一步了解神经发育和RTT病因中的MECP2功能，我们建议（1）表征非CG DNA甲基化如何有助于MECP2功能，（2）研究神经元长度依赖性基因在RTT病理学中的作用。我们希望拟议的实验能够更好地了解MECP2功能，对RTT病因的见识，并最终为发展理论策略的发展提供新的机会，以减轻RTT病理学。