Histone deacetylase 3 modulates Tbx5 activity to regulate early cardiogenesis

Abstract

Congenital heart defects often result from improper differentiation of cardiac progenitor cells. Although transcription factors involved in cardiac progenitor cell differentiation have been described, the associated chromatin modifiers in this process remain largely unknown. Here we show that mouse embryos lacking the chromatin-modifying enzyme histone deacetylase 3 (Hdac3) in cardiac progenitor cells exhibit precocious cardiomyocyte differentiation, severe cardiac developmental defects, upregulation of Tbx5 target genes and embryonic lethality. Hdac3 physically interacts with Tbx5 and modulates its acetylation to repress Tbx5-dependent activation of cardiomyocyte lineage-specific genes. These findings reveal that Hdac3 plays a critical role in cardiac progenitor cells to regulate early cardiogenesis.

Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development

“…Interestingly, embryos lacking HDAC3 in the second heart field display normal ventricular myocardium (data not shown). Previously, we demonstrated that HDAC3 is required in the primary heart field (Nkx2-5 enhancer-Cre) for development of the ventricular myocardium at the early stages of cardiogenesis (48). Taken together, these findings suggest that once the primary heart field progenitors have adopted a cardiac fate to form the nascent heart tube, the second heart field-derived ventricular myocardium can develop independently of HDAC3.…”

“…Previous studies from our group and others have demonstrated that HDACs are critical regulators of various developmental processes, including cardiogenesis (48,49). Among class I HDACs (HDAC1, -2, -3, and -8), global loss of HDAC2 or HDAC8 in mice does not affect morphogenesis of second heart field-derived structures at birth (43,45,46).…”

“…ChIP Analysis-ChIP experiments were performed as described previously (48). Briefly, isolated cardiac tissue or explants from E9.5 mouse embryos were cross-linked for 15 min in cross-linking solution (1% formaldehyde, 1.5 mM ethylene glycol-bis succinimidylsuccinate, 20 mM sodium butyrate, 10% FBS) and then quenched with 125 mM glycine solution for 5 min, followed by two washes with 1ϫ PBS.…”

“…Plasmids and Site-directed Mutagenesis-FLAG-HDAC3 pcDNA3.1(Ϫ) and the FLAG-HDAC3 lentiviral vector were described previously (48). GFP lentiviral vector and lentiviral packaging plasmids were obtained from Addgene: pLOVE-GFP (Addgene plasmid 15949), pCMV-dR8.2 (Addgene plasmid 8455), and pCMV-VSVG (Addgene plasmid 8454).…”

The formation and function of the cardiac conduction system

“…For example, Hdac3, a member of the Class I HDAC family, has been implicated in cardiac development and homeostasis (Montgomery et al, 2008;Singh et al, 2011), acting by repressing the expression of Tbx5 in early development (Lewandowski et al, 2014). During development, it is highly expressed in the SAN (Wu et al, 2014), AVN and Purkinje fibres (Risebro et al, 2012).…”