Exploring Disrupted H3K27me3 in Mendelian Disorders of the Epigenetic Machinery and Restoring Its Balance as a Therapeutic Approach to Treat Abnormal Growth

项目摘要/摘要：成长和神经发育是儿童健康的基本方面。两者都有 在表观遗传机制(MDEM)的孟德尔紊乱中持续中断，这是一组新兴的 由表观遗传机制的组成部分中的基因突变引起的疾病。尽管是个别的 罕见的是，这组障碍占智力残疾(ID)的19%。增长的百分比 MDEM导致的异常尚不清楚，尽管估计有200万至500万美国儿童表现出 异常生长，这是我们新的表观遗传学中看到的MDEM的第二常见表现 和染色质诊所。生长异常可表现为生长迟缓或过度生长； 毁灭性的。目前还没有持续有效的治疗方法。我们最近提出了平衡假说 解释MDEM的分子发病机制，表明各组分之间存在微妙的平衡 单个靶基因的表观遗传机制(以及封闭和开放的染色质状态)，以及 MDEM对这种平衡的干扰可能会改变靶基因的表达。以前的工作 来自我们实验室的科学家支持这一观点，并建议ID的子集可能是可以治疗的，这提出了一个问题 异常生长是否也是可以治疗的。两个MDEM，歌舞伎综合症2(KS2)和Weaver 综合征(WS)的特征是相反的生长异常，KS2表现为生长迟缓 WS表现为过度生长。它们的分子缺陷聚集在相同的组蛋白标记H3K27me3上，并且 以相反的方向扰乱它。我们已经阐明了一种健壮的骨骼生长迟缓表型，并已经 确定了KS2中相关的细胞类型，并建立了一种新的WS小鼠模型。这项建议旨在 使用两种具有相反生长表型和H3K27me3干扰的疾病进行比较 了解这一标记在异常生长中的作用，建立H3K27me3作为疾病和 治疗效果，并制定治疗策略，以影响这一标志，以治疗异常生长。 H3K27me3在涉及异常生长的各种疾病状态下被干扰。因此，瞄准它具有广泛的意义 适用性，并确定异常生长的可治疗形式可以帮助美国各地的儿童A K08 导师临床科学家发展奖将帮助我不仅潜在地影响儿童的生活，而且 我也实现了我的职业目标，成为一名独立调查员和翻译方面的国家权威 表观遗传学。这些都是在约翰·霍普金斯大学严格而有支持性的环境中可以实现的目标 基因医学研究所，我希望从我严谨的职业发展计划中获得的技能，以及 期待我的卓越导师和咨询委员会的支持，其中包括世界知名的 表观遗传病和骨生物学方面的权威。此外，我唯一有资格从事这项工作的人 因为我在表观遗传学和我在小说中的临床活动方面有长期的、多产的背景 表观遗传学和染色质诊所专注于我在实验室研究的疾病，因此将为我的研究提供信息。

Project summary/Abstract:Growth and neurologic development are fundamental aspects of child health. Both are consistently disrupted in Mendelian disorders of the epigenetic machinery (MDEMs), an emerging group of conditions resulting from genetic mutations in components of the epigenetic machinery. Though individually rare, this group of disorders accounts for a striking 19% of intellectual disability (ID). The percentage of growth abnormalities attributable to MDEMs is unknown, though estimates suggest 2-5 million U.S. children exhibit abnormal growth, and it is the second most common manifestation of MDEMs seen in our novel Epigenetics and Chromatin Clinic. Abnormalities of growth can manifest as growth retardation or overgrowth; either can be devastating. No consistently effective treatments exist. We recently proposed the Balance Hypothesis to explain the molecular pathogenesis of MDEMs, suggesting that a delicate balance exists between components of the epigenetic machinery (and closed and open chromatin states) at individual target genes and that perturbation of this balance with a MDEM would be expected to alter target gene expression. Previous work from our laboratory supports this idea and suggests that a subset of ID may be treatable, raising the question of whether abnormal growth also may be treatable. Two MDEMs, Kabuki syndrome 2 (KS2) and Weaver Syndrome (WS), are characterized by opposing growth abnormalities, with KS2 exhibiting growth retardation and WS exhibiting overgrowth. Their molecular defects converge on the same histone mark, H3K27me3, and disrupt it in opposite directions. We have elucidated a robust skeletal growth retardation phenotype and have identified a relevant cell type in KS2, and we have created a novel mouse model of WS. This proposal aims to use a comparison of two disorders with opposing growth phenotypes and disruptions of H3K27me3 to understand the role of this mark in abnormal growth, establish H3K27me3 as a biomarker of disease and therapeutic effect, and develop therapeutic strategies to influence this mark to treat abnormal growth. H3K27me3 is disrupted in diverse disease states involving abnormal growth. Thus targeting it has broad applicability, and identifying treatable forms of abnormal growth could help children across the U.S. A K08 Mentored Clinical Scientist Development Award will help me to not only potentially impact children's' lives, but also achieve my career goals of becoming an independent investigator and a national authority on translational epigenetics. These are achievable goals in the rigorous yet supportive environment in the Johns Hopkins Institute of Genetic Medicine with the skills I expect to gain from my rigorous career development plan and with the support anticipated from my superb mentors and advisory committees, which include world-renowned authorities on epigenetic disease and bone biology. Moreover, I am uniquely qualified to pursue this work because I have a long-standing, productive background in epigenetics, and my clinical activities in the novel Epigenetics and Chromatin Clinic focus on the disorders I study in the lab and will thus inform my research.