MeCP2 and non-CG methylation regulation of neuronal cell-type specific transcription

MeCP2和非CG甲基化对神经元细胞类型特异性转录的调节

• 批准号: 10474264
• 负责人: James Russell Moore
• 金额: $ 5.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474264
• 关键词: Architecture; Binding; Brain; Cells; Characteristics; Chromatin; Complement; CpG dinucleotide; Cytosine; DNA Methylation; Data Analyses; Deposition; Development; Dinucleoside Phosphates; Disease; Enhancers; Ensure; Functional disorder; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Enhancer Element; Genetic Transcription; Genome; Genomic Segment; Genomics; Goals; High-Throughput Nucleotide Sequencing; In Situ; Individual; Intellectual functioning disability; Interneurons; Laboratories; Lead; MeCP2 Duplication Syndrome; Mediating; Methyl-CpG-Binding Protein 2; Methylation; Modeling; Mutation; Nervous system structure; Neurodevelopmental Disorder; Neurons; Parvalbumins; Pathology; Pattern; Proteins; Reader; Regulation; Regulatory Element; Research; Rett Syndrome; Role; Somatostatin; Structure; Testing; Transcription Regulatory Protein; Transcriptional Regulation; Work; autism spectrum disorder; cell type; chromosome conformation capture; experimental study; hippocampal pyramidal neuron; insight; nervous system disorder; neural circuit; neurodevelopment; novel therapeutic intervention; overexpression; programs; response; transcriptome

Project Summary: Mutations in transcriptional regulatory proteins have been identified as a major cause of neurodevelopmental disorders such as autism and intellectual disability. To understand how these proteins drive disease pathology, we need to first develop a mechanistic understanding of how these regulators contribute to normal neurodevelopment. Alterations in methyl-CpG binding protein 2 (MeCP2) results in Rett Syndrome (RTT), a severe neurodevelopmental disorder, and MeCP2 Duplication Syndrome, an autism spectrum disorder. MeCP2 has been shown to bind both methylated CG dinucleotides and a neuron-enriched form of methylation at cytosines in non-CpG contexts (mCA). Loss of MeCP2 leads to increased expression of long neuronal genes (>100kb) that are enriched for mCA within their gene body. Interestingly, mCA and MeCP2 have been shown to regulate gene expression in a cell-type specific manner. The long-term goal of our lab is to understand the function of MeCP2 and mCA transcriptional regulation in the nervous system and how their dysfunction results in neurological disorders. This proposal will determine how MeCP2 and mCA control cell-type specific gene expression programs through control of regulatory elements and in cooperation with genome topology. In Aim 1, I will test the hypothesis that MeCP2 regulates cell-type specific enhancers to drive gene expression programs in individual neurons. In Aim 2, I will further understand this regulatory mechanism by analyzing how chromatin architecture drives cell-type specific mCA patterns. The results from these experiments will provide important insights into the mechanism and function of MeCP2 and mCA and how they produce pathology when disrupted.

项目摘要：转录调节蛋白的突变已被确定为引起 神经发育障碍，如自闭症和智力残疾。为了了解这些蛋白质是如何驱动 疾病病理学，我们需要首先建立一个关于这些调节器如何在 神经发育正常。甲基-CpG结合蛋白2(MeCP2)的改变导致Rett综合征 (RTT)，一种严重的神经发育障碍，以及MeCP2重复综合征，一种自闭症谱系 无序。已证明MeCP2既能结合甲基化的CG二核苷酸，又能结合一种神经元富集型的 非CpG环境中胞嘧啶的甲基化(MCA)。MeCP2基因缺失导致Long基因表达增加 神经细胞基因(&gt；100kb)，在其基因体内富含MCA。有趣的是，MCA和MeCP2 已被证明以细胞类型特异性的方式调节基因表达。我们实验室的长期目标是 了解MeCP2和MCA在神经系统中的转录调控功能以及它们是如何 功能障碍会导致神经紊乱。 这项提案将决定MeCP2和MCA如何控制细胞类型特定的基因表达程序 通过控制调控元件，并与基因组拓扑学合作。在目标1中，我将测试 MeCP2调节细胞类型特异性增强子以驱动个体基因表达程序的假说 神经元。在目标2中，我将通过分析染色质的结构来进一步了解这种调控机制 驱动特定细胞类型的MCA模式。这些实验的结果将为 MeCP2和MCA的机制和功能，以及它们在被干扰时如何产生病理。