T-box transcription factor 3 governs a transcriptional program for the function of the mouse atrioventricular conduction system
Rajiv A. Mohan, Fernanda M. Bosada, Jan Hendrik van Weerd, Karel van Duijvenboden, Jianan Wang, Mathilda T.M. Mommersteeg, Ingeborg B. Hooijkaas, Vincent Wakker, Corrie de Gier-de Vries, Ruben Coronel, Gerard J.J. Boink, Jeroen Bakkers, Phil Barnett, Bastiaan J. Boukens, Vincent M. Christoffels
Abstract
Significance Genome-wide association studies have identified common noncoding variants associated with ECG parameters in the TBX3 locus, suggesting that a modest change in TBX3/Tbx3 expression level affects heart function. We characterized the morphology, physiology, and gene expression profile of the atrioventricular conduction system in a Tbx3 haploinsufficient mouse model. We identified Tbx3-dependent regulatory DNA elements active in the atrioventricular conduction system and validated the functionality of these elements in vivo. Using genome editing, we deleted a regulatory DNA element from the mouse genome and show it drives expression of Cacna1g in the cardiac conduction system. Our study unveils a Tbx3-dependent gene regulatory network in the AV conduction system that contributes to heart electrophysiology.