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Chromatin Mechanisms of Neuronal Maturation

神经元成熟的染色质机制

基本信息

批准号：
9333597
负责人：
Anne Elizabeth West
金额：
$ 44.06万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9333597
关键词：
ARHGEF5 gene Address Adult Autistic Disorder Biological Models Brain Cells Cerebellum ChIP-seq Chromatin Chromatin Structure Clustered Regularly Interspaced Short Palindromic Repeats Cues Cytoplasmic Granules Data Development Distal Enhancers Enzymes Event Foundations Gene Activation Gene Expression Genes Genetic Transcription Genomic DNA Genomics Goals Histone H3 Histones Impairment Intellectual functioning disability Kinetics Knock-out Lysine Mediating Methods Modification Molecular Mus Mutation Neurodevelopmental Disorder Neuronal Differentiation Neurons Phase Phosphorylation Play Population Process Proteins Recruitment Activity Regulation Regulator Genes Regulatory Element Repression Role Sensory Synapses Testing Time Transcriptional Activation Transcriptional Regulation Variant base cell type critical period demethylation derepression epigenetic regulation experimental study gene induction gene product histone methyltransferase in vivo insight knock-down mRNA Expression mouse model neuronal circuitry postnatal programs promoter relating to nervous system selective expression synaptic function

项目摘要

Neuronal differentiation requires the precise orchestration of gene expression programs. Temporal control of transcription is particularly important in maturing postmitotic neurons of the postnatal brain because these cells need to express gene products that refine neuronal function and circuitry during specific critical periods of brain development. Epigenetic regulation of chromatin structure is known to play a role in establishing cell-type specific programs of gene expression during early stages of cell fate determination, but the chromatin mechanisms that regulate gene expression during terminal phases of differentiation remain to be fully understood. The goal of this proposal is to identify chromatin mechanisms that coordinate the induction of genes in maturing neurons of the CNS. To discover these chromatin mechanisms of neuronal differentiation, and to determine how these mechanisms are regulated across multiple stages of neuronal maturation, we have characterized chromatin accessibility, enhancer activation, and gene expression in differentiating cerebellar granule neurons (CGNs) of the postnatal mouse in vivo. We have observed that thousands of regulatory elements show chromatin accessibility changes as CGNs differentiate, and we have verified that many of these differentially accessible regions function as developmental stage-specific enhancers of neuronal genes. Furthermore our data identify a specific group of the genes selectively expressed in mature CGNs of the cerebellum that are associated with repressive histone H3 lysine 27 trimethylation (H3K27me3) at early postmitotic stages of CGN differentiation yet lose this mark as CGNs mature. Consistent with a role for active histone demethylation in the induction of these genes, we find that at least a subset of these genes show increased H3K27me3 and reduced mRNA expression in CGNs lacking the H3K27 demethylase Kdm6b. The overarching hypothesis of this proposal is that the molecular regulators of H3K27me3 dynamics in postmitotic neurons play a key role in timing neuronal maturation. To address this hypothesis we propose the following Specific Aims: 1) To characterize the dynamic demethylation of H3K27 in postmitotic neurons maturing in vivo, 2) To determine the role of the H3K27 demethylase Kdm6b in neuronal maturation, and 3) To identify enhancer mechanisms of transcriptional derepression in maturing neurons. Together these studies will identify the molecular mechanisms that mediate the gene-specific loss of H3K27me3 in maturing CGNs, and they will directly test the importance of the developmental derepression of H3K27me3-silenced genes for functional neuronal maturation.

神经元分化需要基因表达程序的精确编排。的时间控制