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

• 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
• 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

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 ASH 1 L（Absent，Small，or Homeotic discs 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。自闭症谱系大群体的最新遗传学研究 ASH 1 L是ASD的主要危险基因之一。遗传学研究结果进一步支持了 许多临床报告表明，诊断为ASD的儿童获得各种各样的新生ASH 1 L突变。到 为了了解破坏性ASH 1 L突变在ASD发病机制中的致病作用，我们使用了ASH 1 L基因， 条件性敲除（cKO）小鼠，以显示小鼠脑中Ash 1 l的缺失足以引起自闭症- 比如行为和认知记忆缺陷，这表明破坏性的ASH 1 L突变很可能是 与ASD的发生有因果关系我们的以下研究表明，Ash 1 l-KO小鼠发生了一般性神经功能障碍， 多动，表明ASH 1 L的缺失导致神经信号的兴奋/抑制（E/I）不平衡。 个脑袋此外，我们最近的研究报告，出生后给予SAHA，一种组蛋白去乙酰化酶， 抑制剂，改善核心自闭症样行为和认知记忆的阿什11缺陷小鼠，这表明， 组蛋白乙酰化和ASH 1 L介导组蛋白修饰在维持正常 大脑功能基于这些在分子、大脑和生物体水平上的发现，我们提出， ASH 1 L通过其介导的组蛋白修饰促进大脑中的基因表达。ASH 1 L损失 维持大脑E/I平衡的关键基因的表达，从而导致神经系统疾病。 多动和行为缺陷。为了进一步研究表观遗传机制， ASH 1 L在ASD发病机制中的作用，我们将使用Ash 1 l-cKO小鼠来检查ASH 1 L的功能、转录组和表达。 大脑中皮质兴奋性神经元、抑制性神经元和星形胶质细胞的表观基因组。具体而言，我们将（1） 剖析三个神经谱系在促进神经过度活跃和行为方面的功能作用 （2）检查谱系特异性转录组动力学，以确定参与Ash 1 l-KO小鼠中的基因缺陷; Ash 1 l缺陷脑的功能异常;（3）检查谱系特异性表观基因组动态，以确定 ASH 1 L介导的表观遗传机制涉及ASH 1 L缺陷脑的功能异常。 这项研究的完成不仅将大大推进我们对ASH 1 L介导的表观遗传的理解， 调节大脑中基因表达的机制及其在ASD发生中的致病作用，而且 这可能导致开发新的治疗方法来治疗ASH 1 L突变诱导的 神经发育疾病