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

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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.