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

> **NIH NIH K08** · JOHNS HOPKINS UNIVERSITY · 2022 · $20,116

## Abstract

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,
produ...

## Key facts

- **NIH application ID:** 10569853
- **Project number:** 3K08HD086250-04S1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jill A Fahrner
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $20,116
- **Award type:** 3
- **Project period:** 2022-02-10 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10569853

## Citation

> US National Institutes of Health, RePORTER application 10569853, Exploring Disrupted H3K27me3 in Mendelian Disorders of the Epigenetic Machinery and Restoring Its Balance as a Therapeutic Approach to Treat Abnormal Growth (3K08HD086250-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10569853. Licensed CC0.

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