# Understanding how Dot1L activity in the growth plate regulates skeletal growth

> **NIH NIH R03** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $82,000

## Abstract

Abstract
Genes that regulate chromatin organization and function have been implicated in the development of skeletal growth
disorders. A major gap in our current knowledge is how epigenetic regulators control longitudinal bone growth at the
growth plate. From a child's health perspective, a deeper understanding of the role of specific chromatin
modifiers in the postnatal growth plate cartilage may lead to more informed use of targeted epigenetic
therapies that are under investigation for the treatment of pediatric cancers. The goal of our proposal is to
establish the requirement of a chromatin modifier Dot1L (Disruptor of telomere silencing-like 1) in growth plate
cartilage and to uncover transcriptional mechanisms through which it regulates the progression of chondrocyte
differentiation. Dot1L is a unique chromatin modifier because it is the only known enzyme that catalyzes the
methylation of lysine residue 79 in histone 3 (H3K79), an established epigenetic mark for gene transcription. A human
genetic variant of Dot1L is associated with taller pubertal stature and accelerated growth rate in adolescent idiopathic
scoliosis. Recently, inactivation of the Dot1L gene in embryonic cartilage was shown to cause runting, growth plate
disorganization, and early death in mice (1, 2). While inhibition of Dot1L is considered a promising therapy for treatment
of leukemia in children(3-6), we know little about the influence of Dot1L on postnatal growth plate function. Thus, we
developed an inducible strategy to genetically disrupt Dot1L in postnatal growth plate chondrocytes in mice. Postnatal
inactivation of Dot1L in growth plate cartilage using the tamoxifen-inducible Aggrecan-Cre driver (AgcCreERT2) resulted
in an intriguing skeletal phenotype characterized by impaired longitudinal bone growth, structural changes within
growth plate cartilage, and focal closure of the growth plate. Our preliminary in vitro studies further suggest that Dot1L
modulates signaling through the bone morphogenetic protein (Bmp) pathway, a key pathway controlling chondrocyte
differentiation and endochondral ossification. Together, our data reveal a critical and understudied role for Dot1L in
maintaining postnatal GP cartilage. We hypothesize that the chromatin modifier Dot1L maintains the proper
balance of chondrocyte proliferation and maturation to support postnatal bone elongation at the growth
plate. In this study, we will use cutting-edge genetic and molecular approaches to advance our understanding of
Dot1L-mediated regulation of growth plate chondrocyte differentiation and postnatal bone growth by the following
Specific Aims: (1) determine whether postnatal function of Dot1L in the GP restricts chondrocyte maturation; and (2)
identify Dot1L-regulated genes and networks controlling chondrocyte differentiation in the postnatal growth plate. This
contribution is significant since it will advance our understanding of the epigenetic regulation of cartilage genes linked
to human s...

## Key facts

- **NIH application ID:** 9979919
- **Project number:** 5R03HD097426-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Rosaria M. Guzzo
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $82,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979919

## Citation

> US National Institutes of Health, RePORTER application 9979919, Understanding how Dot1L activity in the growth plate regulates skeletal growth (5R03HD097426-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979919. Licensed CC0.

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