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

项目总结/摘要 神经发育障碍（NDD）是一组经常影响大脑发育和功能的疾病。 导致运动、语言、认知和/或社会行为的终身损伤。越来越多的证据表明， 神经发育障碍（NDD），如自闭症的致病机制中的染色质调控 和智力残疾。重要的是，染色质调节剂构成了药理学上有吸引力的群体。 考虑到大多数具有酶活性或可被靶向明确的结合结构域， 这项提案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EZH 1功能增益（GOF）引起的NDD上。 我们最近发现的突变EZH 1及其副产物EZH 2催化组蛋白H3赖氨酸27 甲基化，一种标记和维持转录抑制的染色质修饰。基于我们 根据初步数据，我们提出了一个假设，即这些患者的NDD是由H3 K27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的独特机会。为了验证这个假设， 我们将剖析EZH 1 GOF突变影响神经元发育的细胞和分子机制， 分化（目的1），并确定EZH 1抑制剂具有恢复神经发育缺陷的潜力， EZH 1 GOF突变（Aim 2）。这里获得的结果将作为使用EZH的原理证明 抑制剂治疗由EZH 1 GOF突变引起的NDD，并可能将其应用扩展到其他 具有改变的EZH 1/2和H3 K27 me 3的NDD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.