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 生长和神经发育是儿童健康的基本方面。这两家公司都不断地在 表观遗传机制的孟德尔障碍(MDEM)，一组由以下原因引起的新兴疾病 表观遗传机制组成部分的基因突变。尽管个别情况很少见，但这组疾病 占智力残疾的19%(ID)。可归因于以下原因的生长异常百分比 MDEM尚不清楚，尽管估计有200万至500万美国儿童表现出异常发育，这是 第二个最常见的MDEM表现在我们的新的表观遗传学和染色质临床中。 生长异常可能表现为生长迟缓或过度生长；两者都可能是毁灭性的。不是 一直存在有效的治疗方法。我们最近提出了平衡假说来解释分子 MDEM的发病机制，表明表观遗传成分之间存在微妙的平衡 机制(以及封闭和开放染色质状态)作用于单个靶基因及其扰动 与MDEM的平衡有望改变靶基因的表达。我们实验室以前的工作 支持这一观点，并建议ID的子集可能是可以治疗的，这引发了一个问题，即是否异常 增长也可能是可以治疗的。两种MDEM，歌舞伎综合征2(KS2)和韦弗综合征(WS) 以相反的生长异常为特征，KS2表现出生长迟缓，WS表现出 过度生长。它们的分子缺陷聚集在相同的组蛋白标记H3K27me3上，并以相反的方式破坏它 方向。我们已经阐明了一种健壮的骨骼生长迟缓表型，并发现了相关的 KS2中的细胞类型，我们建立了一种新的WS小鼠模型。这项提案旨在使用比较 H3K27me3基因突变和生长表型相反的两种疾病对此的作用 标记异常生长，建立H3K27me3作为疾病和治疗效果的生物标志物，并开发 影响这一标志的治疗策略，以治疗异常生长。H3K27me3在不同的环境中中断 涉及异常生长的疾病状态。因此，靶向它具有广泛的适用性，并确定了可治疗的方法 异常生长的形式可以帮助美国各地的儿童。A K08指导临床科学家的发展 获奖将帮助我不仅潜在地影响孩子们的生活，而且还将实现我的职业目标 成为翻译表观遗传学的独立研究者和国家权威。这些是 约翰·霍普金斯遗传医学研究所在严格但支持的环境中可实现的目标 有了我期望从我严谨的职业发展计划中获得的技能，以及我期待从 我出色的导师和咨询委员会，其中包括世界知名的表观遗传病专家 和骨生物学。而且，我是唯一有资格从事这项工作的人，因为我有一个长期的， 表观遗传学的生产背景，以及我在新表观遗传学和染色质诊所的临床活动 专注于我在实验室中研究的障碍，从而为我的研究提供信息。

Project Summary 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.