Transcriptional and Epigenetic Regulation of Cardiac Electrophysiology

Abstract

Spatiotemporal gene expression during cardiac development is a highly regulated process. Activation of key signaling pathways involved in electrophysiological programming, such as Notch and Wnt signaling, occurs in early cardiovascular development and these pathways are reactivated during pathologic remodeling. Direct targets of these signaling pathways have also been associated with inherited arrhythmias such as Brugada syndrome and arrhythmogenic cardiomyopathy. In addition, evidence is emerging from animal models that reactivation of Notch and Wnt signaling during cardiac pathology may predispose to acquired arrhythmias, underscoring the importance of elucidating the transcriptional and epigenetic effects on cardiac gene regulation. Here, we highlight specific examples where gene expression dictates electrophysiological properties in both normal and diseased hearts.

Keywords: Electrophysiology; Epigenetics; HEY2; Histone modification; KCNIP2.

Fig. 1

Schematic of chamber-specific “priming” and differential HEY2 expression levels. a Canonical Notch signaling regulates early cardiac development mediated by nuclear translocation of the Notch intracellular domain (NICD), forming a complex with the DNA-binding transcription factor RBP-J (recombination signal binding protein for immunoglobulin kappa J region), MAML (mastermind-like protein), and other coactivators (CoA) to form the Mastermind-containing transcriptional complex at the enhancer region (blue). In the adult during homeostasis, RBP-J is bound to this blue enhancer element in the left ventricle (LV), but not the right ventricle (RV). Upon a pathologic stimulus that reactivates Notch signaling, expression of HEY2 is upregulated only in the “primed” LV, whereas there is no change in HEY2 expression levels in the RV. b Canonical Wnt signaling regulates early cardiac development that is mediated by nuclear translocation of β-catenin (β-cat) forming a complex with the DNA-binding T-cell factor (TCF) and other coactivators at a distinct HEY2 enhancer region (yellow). In the adult during homeostasis, β-catenin is bound to the yellow enhancer in the RV, but not the LV. In reciprocal fashion to Notch signaling, a stimulus that reactivates Wnt signaling results in HEY2 upregulation in the “primed” RV, but no change in HEY2 expression in the LV