Histone deacetylase 3 coordinates deacetylase-independent epigenetic silencing of TGFβ1 to orchestrate second heart field development
Department of Medicine, Division of Cardiovascular Medicine
Cardiovascular Diseases | Cell Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology | Molecular Biology
About two-thirds of human congenital heart disease (CHD) involves second heart field (SHF) 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 Tgfβ1, a causative factor in CHD pathogenesis, in a deacetylase-independent manner to regulate development of SHF-derived structures. In murine embryos lacking Hdac3 in the SHF, increased Tgfβ1 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 Tgfβ signaling causes aberrant endothelial-to-mesenchymal transition (EndMT) and altered extracellular matrix homeostasis in Hdac3-null outflow tracts and semilunar valves and pharmacological inhibition of Tgfβ rescues these defects. Hdac3 recruits components of PRC2 complex, methyltransferase Ezh2, Eed, and Suz12 to the Ncor complex to enrich trimethylation of lys27 on histone H3 at the Tgfβ1 regulatory region and thereby maintains epigenetic silencing of Tgfβ1 specifically within the SHF-derived mesenchyme. Wild-type Hdac3 or catalytically-inactive Hdac3 expression rescue aberrant EndMT and epigenetic silencing of Tgfβ1 in Hdac3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the SHF is a predisposing factor for CHD.
Molecular bases of disease, cardiac development, chromatin regulation, development, epigenetics, gene regulation
DOI of Published Version
Lewandowski, S.L., Janardhan, H.P., and Trivedi, C.M. (2015) Histone deacetylase 3 coordinates deacetylase-independent epigenetic silencing of TGFβ1 to orchestrate second heart field development. The Journal of Biological Chemistry. doi:10.1074/jbc.M115.684753
The Journal of Biological Chemistry
Lewandowski, Sara L.; Janardhan, Harish P.; and Trivedi, Chinmay M., "Histone deacetylase 3 coordinates deacetylase-independent epigenetic silencing of TGFβ1 to orchestrate second heart field development" (2015). GSBS Student Publications. 1950.