ASH1L mediated transcription networks in autism spectrum disorders

自闭症谱系障碍中 ASH1L 介导的转录网络

基本信息

批准号：
10446686
负责人：
Judy Shih-Hwa Liu
金额：
$ 76.05万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
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：
2022-03-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10446686
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 Lead Link Mediating Molecular Morphogenesis Mus Mutant Strains Mice Mutation 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 base cell type confocal imaging density 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 neurodevelopment neuron development neuronal excitability novel patch clamp pre-clinical programs protein expression protein function relating to nervous system risk variant single-cell RNA sequencing synaptic function therapeutic target transcription factor translational approach treatment strategy

项目摘要

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.

抽象的自闭症谱系障碍（ASD）的遗传研究已导致发现了越来越高的高度清单染色质修饰剂和转录因子中的渗透突变。最近的进展提供了一个定义ASD中分子机制的重要机会，并确定新的目标治疗策略。但是，鉴于大量看似独立的ASD风险因素，这是一个主要的 ASD研究的挑战是建立收敛机制，这些机制显然是不同的遗传病因。我们确定了组蛋白 - 甲基转移酶ASH1L之间的新型收敛点，这是一个主要 ASD遗传危险因素和ASD高风险基因簇（例如FOXP1，RIMS1，NRX1A）。我们也发现 ASH1L抵消了PolyComb抑制剂复合物在神经发育中的活性。因此，我们的数据发现与ASD表型基础的细胞和电路功能障碍相关的转录和表观遗传学节点。但是，ASH1L调节导致神经元功能障碍的转录程序是研究了。我们的中心假设是ASH1L抵消了多肉的活性以编排通过调节控制突触功能的转录程序和神经元形态发生。我们将定义ASH1L如何调节神经元的发育和功能。我们将使用多级，协同和翻译的方法，该方法利用人类和鼠标系统确定ASH1L如何调节与ASD发病机理相关的神经元程序。我们定位根据我们强大的初步数据和细胞/分子的专业知识，进行这项工作神经科学，生物信息学，染色质生物学和电生理学。 1）确定ASH1L中的突变如何破坏人类干细胞实验系统中的神经元树木化和功能，2）定义功能和啮齿动物系统中与ASH1L相关的电路表型。 3）定义散装和细胞类型特异性表观遗传学和与ASH1L突变有关的转录特征，引起小鼠和人类的疾病神经元。最后，我们将定义细胞，分子和电生理的救援策略在小鼠和人类实验系统中观察到的表型。