ASH1L mediated transcription networks in autism spectrum disorders

自闭症谱系障碍中 ASH1L 介导的转录网络

• 批准号: 10733409
• 负责人: Judy Shih-Hwa Liu
• 金额: $ 90.61万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733409
• 关键词: ASH1L gene; ATAC-seq; Affect; Bioinformatics; Biology; Brain; Cells; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Corpus Callosum; Data; Defect; Development; Developmental Gene; Disease; Electrocorticogram; Electrophysiology (science); Epigenetic Process; FOXP1 gene; Functional disorder; Gene Expression Profile; Genes; Genetic Predisposition to Disease; Genetic Research; Genetic Transcription; Goals; Histones; Human; Impairment; Intervention; Link; Mediating; Molecular; Morphogenesis; Mus; Mutant Strains Mice; Mutation; Neuroanatomy; Neurodevelopmental Disorder; Neuronal Dysfunction; Neurons; Neurosciences; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Polycomb; Positioning Attribute; Proteins; Repressor Proteins; Research; Risk Factors; Rodent; Role; Slice; Structure; Synapses; System; Testing; Therapeutic; Transferase; Work; autism spectrum disorder; cell type; confocal imaging; density; derepression; disease-causing mutation; gene network; gene repression; genetic risk factor; genome editing; high risk; histone methyltransferase; human stem cells; imaging approach; induced pluripotent stem cell; innovation; interdisciplinary approach; multi-electrode arrays; neural; neurodevelopment; neuron development; neuronal excitability; novel; novel therapeutic intervention; patch clamp; pre-clinical; programs; protein expression; protein function; risk variant; single-cell RNA sequencing; synaptic function; therapeutic target; transcription factor; translational approach; treatment strategy

ABSTRACT Genetic research in autism spectrum disorder (ASD) has led to the discovery of a growing list of highly penetrant mutations in chromatin modifiers and transcription factors. This recent progress provides an important opportunity to define the molecular mechanisms in ASD, as well as to identify targets for new treatment strategies. However, given the large number of seemingly independent ASD risk factors, a major challenge for ASD research is to establish convergent mechanisms that group apparently distinct genetic etiologies. We identified a novel point of convergence between the histone-methyltransferase ASH1L, a major ASD genetic risk factor, and a cluster of ASD high-risk genes (e.g. FOXP1, RIMS1, NRX1a). We also find that ASH1L counteracts the activity of Polycomb repressor complex in neural development. Hence, our data uncover a transcriptional and epigenetic node linked to cell and circuit dysfunction underlying ASD phenotypes. However, the transcriptional programs modulated by ASH1L that lead to neuronal dysfunction are understudied. Our central hypothesis is that ASH1L counteracts Polycomb activity to orchestrate neuronal development by modulating transcriptional programs that control synaptic function and neuronal morphogenesis. We will define how ASH1L regulates neuronal development and function. We will use a multilevel, synergistic and translational approach that leverages human and mouse systems to determine how ASH1L modulates neuronal programs relevant to ASD pathogenesis. We are positioned to undertake this work, based on our robust preliminary data and combined expertise in cellular/molecular neuroscience, bioinformatic, chromatin biology and electrophysiology. 1) Determine how mutations in ASH1L disrupt neuronal arborization and function in human stem cell experimental systems, 2) Define functional and circuit phenotypes associated with ASH1L in rodent systems. 3) Define bulk and cell type specific epigenetic and transcriptional signatures associated with ASH1L mutations that cause disease in mouse and human neurons. Finally, we will define rescue strategies for the cellular, molecular, and electrophysiological phenotypes observed in both mouse and human experimental systems.

摘要 自闭症谱系障碍（ASD）的遗传研究已经发现了越来越多的高度自闭症患者。 染色质修饰剂和转录因子中的渗透突变。这一最新进展提供了一个 这是一个重要的机会，以确定ASD的分子机制，以及确定新的靶点， 治疗策略。然而，考虑到大量看似独立的ASD风险因素， ASD研究面临的挑战是建立趋同机制， 病因学我们确定了组蛋白甲基转移酶ASH1L之间的一个新的会聚点， ASD遗传风险因子和一组ASD高危基因（如FOXP1、RIMS1、NRX1a）。我们还发现 ASH1L在神经发育中抵消Polycomb阻遏复合物的活性。因此，我们的数据 揭示了与ASD表型相关的细胞和回路功能障碍的转录和表观遗传节点。 然而，由ASH1L调节的导致神经元功能障碍的转录程序是 替补演员我们的中心假设是，ASH1L抵消Polycomb活动， 通过调节控制突触功能的转录程序， 神经元形态发生我们将定义ASH1L如何调节神经元的发育和功能。我们将 使用多层次、协同和转化的方法，利用人类和小鼠系统， 确定ASH1L如何调节与ASD发病机制相关的神经元程序。我们的定位是 基于我们强大的初步数据和细胞/分子方面的综合专业知识， 神经科学、生物信息学、染色质生物学和电生理学。1)确定ASH1L中的突变 破坏人类干细胞实验系统中的神经元分支和功能，2）定义功能和 啮齿动物系统中与ASH 1L相关的回路表型。3)定义原液和细胞类型特异性表观遗传 以及与导致小鼠和人类疾病的ASH1L突变相关的转录特征 神经元最后，我们将定义细胞，分子和电生理的拯救策略。 在小鼠和人类实验系统中观察到的表型。