Epigenetic mechanisms of histone methyltransferase ASH1L in autism spectrum disorder

组蛋白甲基转移酶 ASH1L 在自闭症谱系障碍中的表观遗传机制

基本信息

批准号：
10743048
负责人：
Jin He
金额：
$ 51.82万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10743048
关键词：
ASD patient ASH1L gene Acetyltransferase Address Area Astrocytes Behavioral Biochemical Biological Assay Brain CREBBP gene Case Study Cells Child Chromatin Clinical Cognitive Complex Convulsants Defect Development Diagnosis Epigenetic Process Epilepsy Equilibrium Gene Expression Gene Mutation Genes Genetic Genetic study HDAC4 gene Histone Acetylation Histone Deacetylase Inhibitor Histone H3 Histone-Lysine N-Methyltransferase Histones Hyperactivity Impairment In Vitro Individual Induced Mutation Knock-out Knockout Mice Link Lysine Mediating Memory Memory impairment Metabolic Microcephaly Modification Molecular Mus Mutant Strains Mice Mutation Neurodevelopmental Disorder Neurons Pathogenesis Pathogenicity Phenotype Play Process Proteins Reagent Reporting Role Tissue-Specific Gene Expression Transcriptional Regulation Vorinostat autism spectrum disorder autistic autistic behaviour causal variant chromatin modification cohort conditional knockout craniofacial disorder risk epigenetic regulation epigenome excitatory neuron gene network genome-wide histone methyltransferase histone modification inhibitory neuron member mouse model myelination nerve stem cell neural neural circuit neurotransmission novel therapeutic intervention postnatal promoter risk variant skeletal abnormality spatiotemporal success transcription factor transcriptome

项目摘要

Project Abstract ASH1L (Absent, Small, or Homeotic discs 1-Like) is a histone methyltransferase facilitating gene expression through its-mediated chromatin modification. Recent genetic studies on large cohorts of autism spectrum disorder (ASD) patients identify ASH1L is one of top ASD risk genes. The genetic findings are further supported by many clinical reports that children diagnosed with ASD acquire various de novo ASH1L mutations. To understand the pathogenic role of disruptive ASH1L mutations in ASD pathogenesis, we used the Ash1l conditional knockout (cKO) mice to show that deletion of Ash1l in the mouse brain was sufficient to cause autistic- like behaviors and cognitive memory deficits, suggesting that disruptive ASH1L mutations are likely to be causally involved in ASD genesis. Our following studies showed that Ash1l-KO mice developed general neural hyperactivity, suggesting that loss of ASH1L causes excitation/inhibition (E/I) imbalance of neural signals in the brain. Furthermore, our recent study reported that postnatal administration of SAHA, a histone deacetylase inhibitor, ameliorated core autistic-like behaviors and cognitive memory of Ash1l-deficient mice, suggesting that histone acetylation and ASH1L-mediated histone modification have a synergistic function in maintaining normal brain functions. Building upon these discoveries at the molecular, brain, and organismal levels, we propose that ASH1L facilitates gene expression through its-mediated histone modification in the brain. Loss of ASH1L impairs the expression of genes critical for maintaining E/I balance in the brain, which consequently leads to neural hyperactivity and behavioral deficits in Ash1l-KO mice. To further investigate the epigenetic mechanisms of ASH1L in ASD pathogenesis, we will used the Ash1l-cKO mice to examine the function, transcriptome, and epigenome of cortical excitatory neurons, inhibitory neurons, and astrocytes in the brain. Specifically, we will (1) dissect the functional roles of three neural lineages in contributing to the neural hyperactivity and behavioral deficits in Ash1l-KO mice; (2) examine lineage-specific transcriptome dynamics to identify genes involved in the functional abnormalities of the Ash1l-deficient brain; (3) examine lineage-specific epigenome dynamics to identify ASH1L-mediated epigenetic mechanisms involved in the functional abnormalities of the Ash1l-deficient brain. Completion of this study will not only significantly advance our understanding of the ASH1L-mediated epigenetic mechanisms in regulating gene expression in the brain and their pathogenic roles in ASD genesis, but also potentially lead to the development of new therapeutic approaches to treat the ASH1L-mutation-induced neurodevelopmental diseases.

项目摘要 ASH1L（缺失、小或同源异型盘 1-Like）是一种促进基因表达的组蛋白甲基转移酶通过其介导的染色质修饰。最近对自闭症谱系大群体的遗传学研究自闭症谱系障碍 (ASD) 患者认为 ASH1L 是自闭症谱系障碍 (ASD) 的首要风险基因之一。基因研究结果得到进一步支持许多临床报告显示，诊断患有 ASD 的儿童会获得各种新的 ASH1L 突变。到为了了解破坏性 ASH1L 突变在 ASD 发病机制中的致病作用，我们使用了 Ash1l 条件性基因敲除（cKO）小鼠表明，小鼠大脑中 Ash1l 的缺失足以导致自闭症行为和认知记忆缺陷等，表明破坏性 ASH1L 突变可能是因果关系参与自闭症谱系障碍（ASD）的发生。我们的后续研究表明 Ash1l-KO 小鼠发育出一般神经多动症，表明 ASH1L 的缺失会导致神经信号的兴奋/抑制 (E/I) 失衡脑。此外，我们最近的研究报告称，产后服用 SAHA（一种组蛋白脱乙酰酶）抑制剂，改善了 Ash1l 缺陷小鼠的核心自闭症样行为和认知记忆，表明组蛋白乙酰化和 ASH1L 介导的组蛋白修饰在维持正常状态方面具有协同作用大脑功能。基于这些在分子、大脑和有机体水平上的发现，我们提出： ASH1L 通过其介导的大脑中组蛋白修饰促进基因表达。 ASH1L 丢失会造成损害对维持大脑中 E/I 平衡至关重要的基因的表达，从而导致神经 Ash1l-KO 小鼠的多动症和行为缺陷。进一步研究表观遗传机制 ASH1L在ASD发病机制中的作用，我们将使用Ash1l-cKO小鼠来检查其功能、转录组和大脑皮质兴奋性神经元、抑制性神经元和星形胶质细胞的表观基因组。具体来说，我们将 (1) 剖析三种神经谱系在导致神经过度活跃和行为方面的功能作用 Ash1l-KO 小鼠的缺陷； (2) 检查谱系特异性转录组动态，以确定参与谱系特异性的基因 Ash1l 缺陷大脑的功能异常； (3) 检查谱系特异性表观基因组动态以确定 ASH1L 介导的表观遗传机制涉及 Ash1l 缺陷大脑的功能异常。这项研究的完成不仅将显着增进我们对 ASH1L 介导的表观遗传的理解调节大脑基因表达的机制及其在 ASD 发生中的致病作用，而且可能导致开发新的治疗方法来治疗 ASH1L 突变引起的神经发育疾病。