# Regulation of Cardiac Development by Chromatin Modifying Enzymes

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $418,750

## Abstract

Project Summary/Abstract:
Aortic valve disease is an increasingly prevalent cause of morbidity and mortality, with no current effective
pharmacological treatment. An underlying pathology is often aberrant differentiation of valvular interstitial cells
(VICs) leading to altered composition of extracellular matrix (ECM) and calcification. Although various factors
involved in VIC differentiation have been described, the chromatin modifiers required to maintain mesenchymal
identity of VICs remain largely unknown. Histone deacetylases (Hdacs) lack intrinsic DNA-binding domains but
modify chromatin via their interactions with transcription factors, co-factors, and large multiprotein transcriptional
complexes. We recently published that mouse embryos lacking Hdac3 within the second heart field cardiac
progenitor cells exhibit complete embryonic lethality and severe cardiac developmental defects, including
bicuspid and hyperplastic aortic valve. Our preliminary data suggest a novel and unexpected role of Hdac3 in
postnatal aortic valve homeostasis. Hdac3-null aortic valves exhibit upregulation of a discrete set of
chondrogenic genes, which are frequently elevated in human diseased aortic valves. In murine aortic valves,
Hdac3 recruits components of the Polycomb Repressive Complex 2 (PRC2), including methyltransferase Ezh2,
Eed, and Suz12 to enrich trimethylation of lys27 on histone H3 (H3K27me3), a gene silencing mark, at the
regulatory chondrogenic gene loci. The goal of this research program is to identify how Hdac3 regulates
mesenchymal identity of aortic valvular interstitial cells in both humans and mice. In addition, proposed studies
will identify the mechanisms by which different kinases involved in signaling pathways regulate the
phosphorylation, function, and chromatin recruitment of Hdac3. Despite intense study in the area of epigenetics,
very little is known about the role of epigenetic and chromatin modifiers in the field of aortic valve biology. The
set of experiments outlined in this proposal have broad significance not only for understanding how signaling
pathways intersect with chromatin modifiers to regulate homeostasis of aortic valves, but also could be highly
applicable to the entire field of cardiovascular diseases.

## Key facts

- **NIH application ID:** 10399458
- **Project number:** 5R01HL118100-09
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Chinmay M Trivedi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2013-04-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399458

## Citation

> US National Institutes of Health, RePORTER application 10399458, Regulation of Cardiac Development by Chromatin Modifying Enzymes (5R01HL118100-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399458. Licensed CC0.

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