# Histone Proteolysis as a Novel Regulator of Myogenic Activation

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $187,720

## Abstract

ABSTRACT
Developmental signaling cascades ultimately converge in the nucleus to induce broad, yet precise, epigenomic
changes that facilitate the activation of lineage-specific factors necessary for differentiation. One of the
epigenomic changes frequently observed during differentiation, including myogenesis, is the limited proteolysis
of the histone H3 N-terminal tail (H3NT). Although H3NT proteolysis is a common feature of diverse
developmental pathways, the functional significance of this programmed epigenetic event remains largely
undetermined. We recently discovered that H3NT proteolysis occurs during myoblast differentiation and that
matrix metalloproteinase 2 (MMP-2) is the nuclear H3NT protease. Inhibition of MMP-2 activity impaired H3NT
proteolysis concurrent with defective myogenic gene activation and myoblast differentiation. Our findings
support a conceptually innovative model of a novel epigenetic pathway where programmed H3NT proteolysis
at myogenic loci directly facilitates their activation necessary for proficient myogenesis. To test this model we
recently pioneered the first method to identify H3-cleaved (H3cl) loci, called ChIPac-Seq. In Aim 1, ChIPac-Seq
will be leveraged with established cell models to discover the loci selectively targeted for H3NT proteolysis
during myoblast differentiation, which will likely include canonical, and potentially novel, myogenic loci. The
necessity and sufficiency of H3NT proteolysis to facilitate myogenic loci activation and myoblast differentiation
will be determined in Aims 2 and 3, respectively. In Aim 4, our previously reported histone modification and
transcription factor datasets will be leveraged to examine the direct effects of H3NT proteolysis in generating
specific epigenetic changes that promote H3cl loci activation during myoblast differentiation. The anticipated
outcomes of this study will yield foundational insights into the mechanistic functions of H3NT proteolysis as a
novel epigenetic regulator of skeletal muscle development.

## Key facts

- **NIH application ID:** 9830014
- **Project number:** 5R21AR074649-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Brian D Dynlacht
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,720
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830014

## Citation

> US National Institutes of Health, RePORTER application 9830014, Histone Proteolysis as a Novel Regulator of Myogenic Activation (5R21AR074649-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9830014. Licensed CC0.

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