The role of H3K36 methyltransferases on non-CpG methylation patterning in the mammalian brain

H3K36 甲基转移酶对哺乳动物大脑非 CpG 甲基化模式的作用

基本信息

批准号：
10535544
负责人：
Nicole Hamagami-Samson
金额：
$ 3.27万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10535544
关键词：
ASH1L gene Adult Affect Affinity Binding Brain Child Chromatin Clinical DNA Methylation DNA Modification Methylases DNA Modification Process Deposition Development Dinucleoside Phosphates Disease Enhancers Enzymes Epigenetic Process Functional disorder Gene Expression Genes Genetic Genetic Transcription Genetic study Genome Genomic approach Genomics Goals Histones Human Genetics Impairment In Vitro Knockout Mice Knowledge Laboratories Lead Link Mammalian Cell Measures Mediating Methods Methyl-CpG-Binding Protein 2 Methylation Methyltransferase Modeling Modification Molecular Mutant Strains Mice Mutate Mutation Nervous system structure Neurodevelopmental Disorder Neuroglia Neurologist Neurons Outcome PWWP Domain Pathology Pathway interactions Pattern Play Process Publishing Reading Regulation Research Research Training Role Site Syndrome System Testing Training Transcriptional Regulation Up-Regulation Wild Type Mouse Work Writing autism spectrum disorder base brain dysfunction career chromatin modification conditional knockout epigenomics gene regulatory network genome-wide genome-wide analysis genomic data histone methyltransferase histone modification in vivo insight knock-down methylation pattern neurodevelopment neuron development novel programs recruit transcriptome sequencing

项目摘要

Project Summary: Human genetic studies have linked autism and related neurodevelopmental disorders (NDD) to disruption of genes encoding epigenetic factors. While mutations in these genes can affect more than one pathway that leads to ASD, identification of a common molecular pathway across genetic causes of ASD can provide insight into broadly applicable therapies. Recent evidence from our laboratory suggests that a neuronal-specific form of DNA methylation is a shared epigenetic modification that is disrupted in ASD-associated neurodevelopmental disease. Though DNA methylation is classically considered to only occur in mammalian cells in the CpG context, neurons are uniquely enriched for methylation in non-CpG contexts established by DNMT3A. This non-CpG methylation primarily occurs at CA dinucleotides (mCA) and is critical for proper neuronal development and function. Though mCA plays an important role in regulating neuronal gene expression, it is not known how the mCA landscape is faithfully established across the neuronal genome, and whether additional NDDs involve disruption of mCA. Recent studies outside the nervous system have suggested that histone modifications may play a central role in directing DNMT3A-mediated DNA methylation across the genome, but it is not known to how these histone modifications influence DNMT3A and mCA throughout the neuronal genome. Intriguingly, mutations in H3K36 histone methyltransferases have been recently identified in ASD gene studies. Additionally, recent studies conducted outside the nervous system have suggested that H3K36 methylation recruits DNMT3A and regulates its activity. In this proposal, I will determine how disruption of H3K36 methylation-mediated interactions with DNMT3A disturbs critical patterns of mCA across the neuronal genome to drive brain dysfunction. In Aim 1, I will disrupt NDD-relevant H3K36 methyltransferases and measure how DNMT3A recruitment and mCA are affected. This will define the mechanisms underlying histone and DNA modification dynamics on regulating neuronal transcription and building our basic understanding of how disruption of mCA drives disease. In Aim 2, I will explore how loss of H3K36 dimethylase NSD1 causes dysregulation of neuronal genes via shared neuronal chromatin pathology observed across heterogenous clinical syndromes of ASD. I will use genomic approaches to examine how altered DNA methylation as a result of NSD1 loss affects enhancer activity to drive transcriptional dysregulation in nervous system dysfunction and disease. This analysis will begin to identify key downstream chromatin associated factors across a common molecular pathway involved in multiple genetic causes of ASD to provide insight into functional cellular outcomes and broadly applicable therapies.

项目摘要：人类遗传研究已将自闭症和相关神经发育障碍（NDD）联系起来编码表观遗传因子的基因。而这些基因中的突变会影响导致的多个途径至ASD，识别跨ASD遗传原因的常见分子途径可以提供洞察力广泛适用的疗法。我们实验室的最新证据表明，DNA的神经元特异性形式甲基化是一种共同的表观遗传修饰，在与ASD相关的神经发育疾病中受到破坏。尽管在CPG环境中，通常认为DNA甲基化仅在哺乳动物细胞中发生，但在DNMT3A建立的非CPG环境中，神经元独特地富含甲基化。这个非CPG 甲基化主要发生在CA二核苷酸（MCA），对于适当的神经元发育至关重要功能。尽管MCA在调节神经元基因表达方面起着重要作用，但尚不知道如何 MCA景观是在整个神经元基因组中忠实建立的，以及其他NDD是否涉及 MCA的破坏。神经系统之外的最新研究表明，组蛋白修饰可能在引导DNMT3A介导的DNA甲基化跨基因组中起着核心作用，但尚不清楚这些组蛋白的修饰如何影响整个神经元基因组的DNMT3A和MCA。有趣的是，最近在ASD基因中鉴定出H3K36组蛋白甲基转移酶的突变研究。此外，在神经系统之外进行的最近进行的研究表明，H3K36 甲基化募集DNMT3A并调节其活性。在此提案中，我将确定H3K36的破坏程度如何甲基化介导的与DNMT3A的相互作用在神经元基因组中扰乱了MCA的临界模式推动大脑功能障碍。在AIM 1中，我将破坏与NDD相关的H3K36甲基转移酶，并测量如何 DNMT3A招聘和MCA受到影响。这将定义组蛋白和DNA的基础机制修改有关调节神经元转录并建立我们对如何如何的理解的动态 MCA的破坏驱动疾病。在AIM 2中，我将探讨H3K36二甲基酶NSD1的损失神经元基因的失调通过在异质临床上观察到的共同神经元染色质病理 ASD综合征。我将使用基因组方法来检查NSD1导致的DNA甲基化如何改变损失会影响增强子活性，以驱动神经系统功能障碍和疾病中的转录失调。该分析将开始识别公共分子的关键下游染色质因子涉及多种遗传原因ASD的途径，以洞悉功能性细胞结局和广泛适用的疗法。