ASH1L mediated transcription networks in autism spectrum disorders

项目摘要 自闭症谱系障碍（ASD）的研究导致了染色质中高度渗透突变的发现 修饰因子和转录因子。然而，考虑到ASD风险因素的大量存在， ASD研究是建立趋同机制，分组明显不同的遗传病因。我们 确定了一个新的聚合点之间的组蛋白甲基转移酶ASH 1 L，一个主要的ASD遗传 危险因素和一组ASD高危基因（如FOXP 1、RIMS 1、NRX 1 α）。转录程序 导致神经元功能障碍的ASH 1 L调控机制尚不清楚。我们的研究揭示了 与ASD表型相关的细胞和回路功能障碍有关的转录和表观遗传节点。我们 中心假设是ASH 1 L抵消Polycomb（PRC 2）活动以协调神经元 通过调节控制突触功能和神经元功能的转录程序 形态发生我们已经观察到，ASH 1 L缺陷的神经元显示出显著降低的 FOXP 1表达，表明ASH 1 L对FOXP 1的转录控制。因此，这可能是 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。 FOXP 1和ASH 1 L缺陷引起的网络。在本附录中，我们将测试ASH 1 L 通过抑制PRC 2调节下游靶点FOXP 1介导的转录程序 活动我们将确定FOXP 1如何在两个目标中对ASH 1 L突变表型做出贡献。目标1： 将通过描述形态和解剖学特征来识别会聚和发散机制， ASH 1 L和FOXP 1突变小鼠脑的表型。在目标2中，我们将定义 ASH 1 L和FOXP 1神经元转录网络，包括PRC 2的参与， ASH 1 L和FOXP 1缺陷小鼠脑的转录组学分析。这些目标不仅将提供更清晰的 深入了解我们对ASH 1 L介导的神经元发育机制的研究，也构成了 本多样性补充的研究培训组成部分，为我们的学士后研究助理。资金 将允许我们的研究助理融入我们的ASH 1 L研究团队，同时获得 在组织学技术和先进的显微镜，分子表达分析和 生物信息学沿着会议活动和接触严谨，道德，科学交流和 翻译研究的要素，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强大MD/PhD课程做准备。

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.