ASH1L mediated transcription networks in autism spectrum disorders

摘要 对自闭症谱系障碍(Asd)的基因研究导致发现了越来越多的高度 染色质修饰物和转录因子的穿透性突变。这一最新进展提供了一种 定义ASD的分子机制以及确定新的靶点的重要机会 治疗策略。然而，鉴于大量看似独立的ASD风险因素，一个主要的 ASD研究面临的挑战是建立聚合机制，将明显不同的基因组合在一起 病因学。我们发现了一个新的聚合点，在组蛋白-甲基转移酶Ash11之间，一个主要的 ASD遗传风险因素，以及一组ASD高危基因(如Foxp1、RIMS1、NRX1a)。我们还发现， Ash11在神经发育中抵消多梳抑制物复合体的活性。因此，我们的数据 发现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。 然而，由Ash1调节的导致神经元功能障碍的转录程序是 未得到充分研究。我们的中心假设是，Ash11抵消了Polycomb活动来协调 通过调节转录程序控制突触功能和神经元发育 神经元形态发生。我们将定义Ash1如何调节神经元的发育和功能。我们会 使用多层次、协同和转换的方法，利用人类和鼠标系统 确定Ash1l如何调节与ASD发病相关的神经元程序。我们的定位是 根据我们强大的初步数据和细胞/分子方面的综合专业知识，开展这项工作 神经科学、生物信息学、染色质生物学和电生理学。1)确定Ash1l的突变如何 扰乱人类干细胞实验系统中神经元的分枝和功能，2)定义功能和 啮齿动物系统中与Ash1相关的回路表型。3)定义批量和细胞类型特定的表观遗传学 以及与在小鼠和人类中导致疾病的Ash11突变相关的转录特征 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都观察到了表型。

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.