ASH1L mediated transcription networks in autism spectrum disorders

项目摘要 自闭症谱系障碍(ASD)研究导致发现染色质高度穿透性突变 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研究旨在建立将明显不同的遗传病因归类的汇聚机制。我们 发现了组蛋白-甲基转移酶Ash11之间的一个新的聚合点，组蛋白-甲基转移酶Ash11是ASD的一个主要基因 危险因素，以及一组自闭症高危基因(如Foxp1，RIMS1，NRX1α)。转录程序 由Ash1调节导致神经元功能障碍的机制目前还知之甚少。我们的研究揭示了一个 转录和表观遗传结节与ASD表型下的细胞和回路功能障碍有关。我们的 中心假说是Ash11中和Polycomb(PRC2)活动来协调神经元 调节调节突触功能和神经元的转录程序的发育 形态发生。我们已经观察到，缺乏Ash11的神经元显示出显著降低的 Foxp1的表达，表明了Ash1对Foxp1的转录调控。因此，这是有可能的 关系是大脑结构变化及其相关转录变化中重叠特征的基础 由Foxp1和Ash1缺乏引起的网络。在这份补充材料中，我们将检验以下假设 通过抑制PRC2来调节其下游靶标Foxp1介导的转录程序 活动。我们将从两个方面确定Foxp1对Ash1突变表型的贡献。在目标1中，我们 将通过表征形态和解剖学特征来识别收敛和发散机制 Ash1和Foxp1突变小鼠脑的表型。在目标2中，我们将定义 Ash1和Foxp1神经元转录网络，包括PRC2的参与，通过执行 Ash1和Foxp1基因缺陷小鼠脑的转录分析。这些目标不仅将提供更清晰的 深入了解Ash11介导的神经元发育机制，也构成了 这是为我们毕业后的研究助理编写的多样性补充资料中的研究培训部分。基金 将允许我们的研究助理融入我们的Ash1研究团队，同时获得 在组织学技术和高级显微镜、分子表达分析和 生物信息学。除了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 准备进入神经科学研究领域的MD/PHD课程。

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.