ArticleThe Journal of biological chemistry2015
Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 93 citations in OpenAlex.
- Histone deacetylase enzyme activity is not the universal anticancer target of HDAC inhibitors.Signal transduction and targeted therapy · 2026Article
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- EndMT in vascular cognitive impairment and dementia: mechanisms, evidence gaps, and therapeutic opportunities.Molecular medicine (Cambridge, Mass.) · 2026Review
- HDAC3-driven immunometabolic reprogramming in type 2 diabetes and its complications: from enzymatic deacetylation to non-enzymatic scaffolding.Frontiers in immunology · 2026Review
- Catalytic-independent roles of chromatin modifiers in mammalian development and the implications for treating human disease.Biochemical Society transactions · 2025Review
- Bicuspid Aortic Valve in Heritable Thoracic Aortic Disease: Insights from the Montalcino Aortic Consortium.medRxiv : the preprint server for health sciences · 2025Article
- Unlocking cardiac health: exploring the role of class I HDACs in cardiovascular diseases.Molecular and cellular biochemistry · 2025Review
- Epigenetic dysregulation of energy homeostasis drives aortic valve stenosis that is treatable with metformin.JCI insight · 2025Article
- Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway.Journal of advanced research · 2025Article
- Enzyme-independent functions of HDAC3 in the adult heart.Acta pharmaceutica Sinica. B · 2025Article
- Epigenetic Mechanisms in Heart Diseases.Reviews in cardiovascular medicine · 2025Review
- Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology.International journal of molecular sciences · 2024Review
- Mechanism Exploration of Euphorbia fischeriana Steud. for Liver Cancer Based on Aspartic Acid Identification in Metabolomics.Chinese journal of integrative medicine · 2024Article
- Endocardial HDAC3 is required for myocardial trabeculation.Nature communications · 2024Article
- Epigenetic determinants and non-myocardial signaling pathways contributing to heart growth and regeneration.Pharmacology & therapeutics · 2024Review
- The impact of selective HDAC inhibitors on the transcriptome of early mouse embryos.BMC genomics · 2024Article
- Targeting histone deacetylase in cardiac diseases.Frontiers in physiology · 2024Review
- Integrated Pathogenesis of Vascular and Cardiac Valve Disease.Circulation research · 2023Article
- Separation of transcriptional repressor and activator functions in Drosophila HDAC3.Development (Cambridge, England) · 2023Article
- Bicuspid aortic valve aortopathy is characterized by embryonic epithelial to mesenchymal transition and endothelial instability.Journal of molecular medicine (Berlin, Germany) · 2023Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.
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