Leveraging a newly identified EZH1 associated syndrome to explore pharmacological recovery of neurodevelopmental disorders

项目摘要/摘要 神经发育障碍(NDDS)是一组经常影响大脑发育和功能的疾病 导致终身运动、语言、认知和/或社会行为障碍。越来越多的证据涉及 染色质调节在自闭症等神经发育障碍(NDDS)发病机制中的作用 和智力残疾。重要的是，染色质调节剂构成了一个有吸引力的药理学群体。 干预，因为大多数港湾酶活性或明确定义的结合域，可以作为靶点。 这项建议的首要目标是确定和测试一类新的染色质的治疗潜力。 调节剂化合物。特别是，我们的工作将集中在由EZH1功能增益(GOF)引起的NDD 我们最近发现的突变。EZH1及其类似物EZH2催化组蛋白H3赖氨酸27 甲基化，一种染色质修饰，标记并维持转录抑制。基于我们的 初步数据我们提出的假设是，这些患者的NDD是由H3K27的调节失调引起的 甲基化导致神经元分化基因的异常转录抑制。因此，我们设想 使用EZH抑制剂对这种患者进行药物治疗是一个独特的机会。为了检验这一假设， 我们将剖析EZH1 GOF突变在神经元发育过程中影响的细胞和分子机制 分化(目标1)并确定具有修复神经发育缺陷潜力的EZH1抑制剂 通过EZH1 GOF突变(目标2)。所得结果将为EZH的使用提供原则性的证明 用于治疗由EZH1 GOF突变引起的NDDS的抑制剂，并有可能将其应用于其他 EZH1/2和H3K27me3基因突变的NDDS介导转录抑制。

PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) are a group of conditions that affect brain development and function often leading to lifelong impairments in motor, language, cognitive and/or social behaviors. Increasing evidence involve chromatin regulation in the pathogenic mechanism of neurodevelopmental disorders (NDDs), such as autism and intellectual disabilities. Importantly, chromatin regulators constitute an attractive group for pharmacological intervention given that most harbor enzymatic activities or well-defined binding domains that can be targeted. The overarching goal of this proposal is to identify and test the therapeutic potential of a novel class of chromatin regulator compounds. In particular our work will be focused on a NDD caused by EZH1 gain of function (GOF) mutations that we have recently identified. EZH1, and its paralogue EZH2, catalyze histone H3 Lysine 27 methylation, a chromatin modification that marks and maintains transcriptional repression. Based on our preliminary data we propose the hypothesis that the NDD in these patients is caused by dysregulation of H3K27 methylation leading to abnormal transcriptional repression of neuronal differentiation genes. Thus, we envision a unique opportunity for pharmacological treatment of this patients using EZH inhibitors. To test this hypothesis, we will dissect cellular and molecular mechanisms affected by EZH1 GOF mutations during neuronal differentiation (Aim 1) and identify EZH1 inhibitors with potential to restore neurodevelopmental defects caused by EZH1 GOF mutations (Aim 2). Results obtained here will serve as a proof of principle for the use of EZH inhibitors to treat NDDs caused by EZH1 GOF mutations and potentially extend their application to other NDDs with altered EZH1/2 and H3K27me3 mediated transcriptional repression.