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: 10819810
• 负责人: Judy Shih-Hwa Liu
• 金额: $ 3.51万
• 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/10819810
• 关键词: ASH1L gene; Administrative Supplement; Admission activity; Anatomy; Bioinformatics; Brain; Cells; Chromatin Remodeling Factor; Communication; Doctor of Philosophy; Elements; Epigenetic Process; Ethics; Exposure to; FOXP1 gene; Functional disorder; Funding; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Transcription; Histological Techniques; Link; Mediating; Microscopy; Molecular; Morphogenesis; Morphology; Mus; Mutant Strains Mice; Mutation; Neuronal Dysfunction; Neurons; Neurosciences Research; Phenotype; Polycomb; Postbaccalaureate; Preparation; Research; Research Assistant; Research Training; Risk Factors; Role; Structure; Testing; Training; Transcriptional Regulation; Translational Research; autism spectrum disorder; career development; disease phenotype; experience; genetic risk factor; high risk; histone methyltransferase; insight; mutant; neuron development; novel; programs; risk variant; symposium; synaptic function; transcription factor; transcriptomics

Project Summary Autism spectrum disorder (ASD) research has led to the discovery of highly penetrant mutations in chromatin modifiers and transcription factors. However, given the large number of 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, NRX1α). Transcriptional programs modulated by ASH1L that lead to neuronal dysfunction are poorly understood. Our studies uncover a transcriptional and epigenetic node linked to cell and circuit dysfunction underlying ASD phenotypes. Our central hypothesis is that ASH1L counteracts Polycomb (PRC2) activity to orchestrate neuronal development by modulating transcriptional programs governing synaptic function and neuronal morphogenesis. We have observed that ASH1L-deficient neurons show significantly decreased levels of FOXP1 expression, indicating transcriptional control of FOXP1 by ASH1L. It is therefore possible that this relationship underlies overlapping features in the changes in brain structure and their associated transcriptional networks caused by FOXP1 and ASH1L deficiency. In this Supplement, we will test the hypothesis that ASH1L regulates transcriptional programs mediated by its downstream target, FOXP1, via inhibition of PRC2 activity. We will determine how FOXP1 contributes to the ASH1L mutant phenotype in two Aims. In Aim 1, we will identify convergent and divergent mechanisms by characterizing the morphological and anatomical phenotypes of ASH1L and FOXP1 mutant mouse brains. In Aim 2, we will define the relationship between ASH1L and FOXP1 neuronal transcriptional networks, including the involvement of PRC2, by performing transcriptomic analysis of ASH1L and FOXP1-deficient mouse brains. These Aims will not only provide clearer insight into our studies of ASH1L-mediated mechanisms of neuronal development, but also constitute the research training component of this Diversity Supplement for our post-baccalaureate research assistant. Funds from the Supplement will allow our research assistant to integrate into our ASH1L research team while gaining bench experience in histological techniques and advanced microscopy, molecular expression analysis and bioinformatics. Along with conference activities and exposure to rigor, ethics, scientific communication and elements of translational research, our assistant will receive career development training and guidance in preparation for admission to a strong MD/PhD program in neuroscience research.

项目概要 自闭症谱系障碍 (ASD) 研究发现了染色质的高度渗透性突变 然而，鉴于自闭症谱系障碍 (ASD) 风险因素数量众多，这是一个重大挑战 ASD 研究旨在建立将明显不同的遗传病因分组的趋同机制。 确定了组蛋白甲基转移酶 ASH1L（一种主要的 ASD 基因）之间的一个新的聚合点 风险因素，以及一组 ASD 高风险基因（例如 FOXP1、RIMS1、NRX1α）。 我们的研究揭示了 ASH1L 调节导致神经元功能障碍的原因知之甚少。 转录和表观遗传节点与 ASD 表型背后的细胞和电路功能障碍有关。 中心假设是 ASH1L 抵消 Polycomb (PRC2) 活动以协调神经 通过调节控制突触功能和神经元的转录程序来发育 我们观察到 ASH1L 缺陷的神经元表现出显着降低的水平。 FOXP1 表达，表明 ASH1L 对 FOXP1 进行转录控制。 这种关系是大脑结构变化及其相关转录的重叠特征的基础 FOXP1 和 ASH1L 缺陷引起的网络在本补充材料中，我们将检验 ASH1L 的假设。 通过抑制 PRC2 来调节由下游靶标 FOXP1 介导的转录程序 我们将确定 FOXP1 如何在两个目标中对 ASH1L 突变表型做出贡献。 将通过表征形态和解剖学来识别趋同和发散机制 ASH1L 和 FOXP1 突变小鼠大脑的表型 在目标 2 中，我们将定义之间的关系。 ASH1L 和 FOXP1 神经转录网络，包括 PRC2 的参与，通过执行 对 ASH1L 和 FOXP1 缺陷小鼠大脑进行转录组分析不仅会提供更清晰的结果。 深入了解我们对 ASH1L 介导的神经发育机制的研究，同时也构成了 我们的学士后研究助理的多样性补充的研究培训部分。 补充材料将使我们的研究助理能够融入我们的 ASH1L 研究团队，同时获得 在组织学技术和先进显微镜、分子表达分析和 以及生物信息学以及会议活动和严谨性、道德、科学交流和接触。 转化研究的要素，我们的助理将接受职业发展培训和指导 为进入神经科学研究领域的医学博士/博士课程做好准备。