Differential Wnt-mediated Programming and Arrhythmogenesis in Right versus Left Ventricles [wntlof]

Several inherited arrhythmias primarily affect the right ventricle, including Brugada syndrome and arrhythmogenic cardiomyopathy, however the molecular basis of this chamber predilection is not well understood. Right and left ventricular cardiomyocytes derive from distinct progenitor populations. Here, we show that Hrt2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle and Notch signaling in the left ventricle. Perturbations of Wnt and Notch signaling during development and in the adult lead to chamber-specific transcriptional effects on Hrt2 expression associated with distinct binding patterns to Hrt2 enhancers. Differential enhancer binding is present at early developmental stages when the signaling pathways are active and persists into adulthood. Consistent with chamber-specific regulation, mice deficient in Wnt transcriptional activity dysregulate only a small fraction of transcripts in common between ventricles. Wnt target gen es important for cellular electrophysiology are differentially regulated, resulting in perturbed cardiac conduction and cellular electrophysiological parameters only within the right ventricle. Ex vivo and in vivo physiologic stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. Taken together, these data delineate mechanisms underlying ventricular-specific arrhythmia susceptibility due to embryonic programming. RNA-seq data of Wnt LOF RV and LV n=3 for each group (control lv, control rv, wntlof lv, wntlof rv)