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MECHANISMS OF EPIGENETIC REGULATION IN NERVOUS SYSTEM DEVELOPMENT

神经系统发育中的表观遗传调控机制

基本信息

批准号：
10338119
负责人：
Harrison W Gabel
金额：
$ 39.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-14 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338119
关键词：
Affect Automobile Driving Binding Brain Candidate Disease Gene Cell Culture System Cell physiology Centers for Disease Control and Prevention (U.S.)Cerebral cortex Chromatin Chromatin Structure CpG dinucleotide Cytosine DNA DNA Methylation DNA Modification Methylases DNA Sequence Alteration Deposition Dinucleoside Phosphates Disease Enhancers Enzymes Epigenetic Process Functional disorder Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genetic study Genome Genomics Goals Histone Acetylation Human Genetics In Vitro Individual Intellectual functioning disability Interneurons Lead Mediating Methyl-CpG-Binding Protein 2 Methylation Missense Mutation Molecular Mus Mutant Strains Mice Mutation Nature Nervous System Physiology Nervous system structure Neurodevelopmental Disorder Neurons Nuclear Parvalbumins Pathway interactions Phenotype Population Proteins Regulator Genes Regulatory Pathway Role Severities Site Syndrome System Testing Transcriptional Regulation Transgenic Mice United States Work autism spectrum disorder base cell type disease-causing mutation epigenetic regulation excitatory neuron gene function genome-wide analysis in vivo individuals with autism spectrum disorder inhibitory neuron insight mammalian genome molecular pathology molecular site mutant nervous system development neurodevelopment novel postnatal development protein expression public health relevance therapeutic development transcriptome sequencing

项目摘要

Abstract Advances in human genetics have led to the identification of a large number of genes associated with autism spectrum disorder (ASD), intellectual disability (ID), and related neurodevelopmental diseases. A critical new challenge is to understand the molecular pathways these genes contribute to in neurons and to dissect how their disruption alters nervous system function. Methylation of cytosines in DNA classically occurs only at CG dinucleotides, but recent studies have also uncovered functions for unique non-CpG DNA methylation in neurons (which occur largely at CA dinucleotides, mCA). We have discovered that the methyl-DNA-binding protein MeCP2, which is critical for proper nervous system function, binds to mCA within the transcribed regions of genes in neurons to downregulate their expression. New studies have identified mutations in DNMT3A, the DNA methyltransferase required for the deposition of mCA in the brain, in individuals with ID and ASD. These findings support the hypothesis that disruption of gene regulation mediated by mCA contributes to disorders caused by mutation of DNMT3A. Our proposed studies will test this hypothesis by pursuing three specific aims: Aim 1 will use in vitro cell culture systems to determine how disease-associated mutations in DNMT3A affect enzyme function and alter deposition of mCA in neurons. Aim 2 will employ newly-generated transgenic mice carrying heterozygous mutations in DNMT3A to determine the effects of this disruption on neuronal DNA methylation, chromatin structure, transcription and cellular functions. Aim 3 will interrogate the mechanisms by which mCA and MeCP2 directly regulate transcription in neurons, testing the hypothesis that these components interact with novel gene-regulatory sites to control transcription. Together these studies will determine the molecular mechanisms by which mCA regulates gene expression in neurons, and define a site of molecular pathology in ASD and ID.

摘要：人类遗传学的进步已导致鉴定出大量与…相关的基因