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.

项目摘要 自闭症谱系障碍（ASD）研究导致发现了高度渗透突变 修饰符和转录因子。但是，鉴于大量的ASD风险因素，这是一个重大挑战 ASD研究是建立分组明显不同遗传病因的收敛机制。我们 确定了Hisstone-甲基转移酶ASH1L（主要ASD遗传）之间的新颖融合点 风险因素和ASD高风险基因簇（例如FOXP1，RIMS1，NRX1α）。转录程序 由ASH1L调节导致神经元功能障碍的调节知之甚少。我们的研究发现了 转录和表观遗传学节点与ASD表型的细胞和电路功能障碍相关。我们的 中心假设是ASH1L抵消PolyComb（PRC2）活性以编排神经元 通过调节控制突触功能和神经元的转录程序来开发 形态发生。我们观察到ASH1L缺陷神经元显示出显着提高的水平 FOXP1表达，表明ASH1L对FOXP1的转录控制。因此，有可能 关系是大脑结构变化及其相关转录的重叠特征的基础 由FOXP1和ASH1L缺乏引起的网络。在此补充中，我们将测试ASH1L的假设 通过抑制PRC2，调节其下游目标FOXP1介导的转录程序 活动。我们将确定FOXP1在两个目标中如何促进ASH1L突变体表型。在AIM 1中，我们 通过表征形态和解剖学来识别收敛和分歧的机制 ASH1L和FOXP1突变体小鼠大脑的表型。在AIM 2中，我们将定义 ASH1L和FOXP1神经元转录网络，包括PRC2的参与，通过执行 ASH1L和FOXP1缺陷小鼠大脑的转录组分析。这些目标不仅会更清晰 深入了解我们对ASH1L介导的神经元发展机制的研究，但也构成 这种多样性补充的研究培训组成部分是我们的后龙研究助理。资金 补充剂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 基于组织学技术和晚期显微镜，分子表达分析和 生物信息学。以及会议活动以及对严格，道德，科学沟通和 转化研究的要素，我们的助手将获得职业发展培训和指导 准备在神经科学研究中接受强大的MD/PHD计划的准备。