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.

Public Health Relevance

Aortic and pulmonic valve defects are the most commonly occurring heart developmental defects in humans. Our exciting findings reveal a novel function of DNA modifying enzyme during valve development. The set of experiments outlined in this proposal will reveal important molecular mechanisms underlying valve development and disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Acharya, Diwash; Nera, Bernadette; Milstone, Zachary J et al. (2018) TIP55, a splice isoform of the KAT5 acetyltransferase, is essential for developmental gene regulation and organogenesis. Sci Rep 8:14908
Zelic, Matija; Roderick, Justine E; O'Donnell, Joanne A et al. (2018) RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J Clin Invest 128:2064-2075
Janardhan, Harish P; Milstone, Zachary J; Shin, Masahiro et al. (2017) Hdac3 regulates lymphovenous and lymphatic valve formation. J Clin Invest 127:4193-4206
Milstone, Zachary J; Lawson, Grace; Trivedi, Chinmay M (2017) Histone deacetylase 1 and 2 are essential for murine neural crest proliferation, pharyngeal arch development, and craniofacial morphogenesis. Dev Dyn 246:1015-1026
Lewandowski, Sara L; Janardhan, Harish P; Trivedi, Chinmay M (2015) Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-?1 (TGF-?1) to Orchestrate Second Heart Field Development. J Biol Chem 290:27067-89
Kayyali, Usamah S; Larsen, Christopher G; Bashiruddin, Sarah et al. (2015) Targeted deletion of Tsc1 causes fatal cardiomyocyte hyperplasia independently of afterload. Cardiovasc Pathol 24:80-93
Lewandowski, Sara L; Janardhan, Harish P; Smee, Kevin M et al. (2014) Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis. Hum Mol Genet 23:3801-9