# 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 · 2020 · $169,369

## Abstract

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-standi...

## Key facts

- **NIH application ID:** 10011927
- **Project number:** 5K08HD086250-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jill A Fahrner
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,369
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011927

## Citation

> US National Institutes of Health, RePORTER application 10011927, Exploring Disrupted H3K27me3 in Mendelian Disorders of the Epigenetic Machinery and Restoring Its Balance as a Therapeutic Approach to Treat Abnormal Growth (5K08HD086250-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10011927. Licensed CC0.

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