Chd4 and Zbtb7b cooperate to inhibit Cardiac Arrhythmia by repressing Cornifin-A expression

Abstract

Abstract Cardiac arrhythmias are life-threatening pathologies worldwide, but their etiology and development are still under debate. We have recently described that the Chd4/NuRD chromatin-remodeling complex is one of the epigenetic regulators involved in the maintenance of cardiac muscle identity. Indeed, conditional cardiomyocyte deletion of Chd4 (Chd4cKO) in mice induces arrhythmias, in part due to aberrant expression of the skeletal muscle sarcomeric gene program in differentiating and terminally differentiated cardiomyocytes (Gomez-del Arco et al. 2016 and El Abdellaoui-Soussi, 2022). In addition, we also discovered that numerous cardiac conduction system (CCS)-specific genes such as Hcn4, Cntn2, Cx43, Cx40, among others, were deregulated in these mutant mice. To better characterize the triggers of arrhythmogenesis in these Chd4cKO mice, we performed an in silico search for transcription factors (TFs) interacting with Chd4 in the heart and found that Zbtb7b could be one of these TFs. We therefore generated cKO mice for both genes and found that the arrhythmias appearing in the Chd4/Zbtb7b double KO (dKO) were much more severe than in the Chd4cKO and, therefore, dKO animals succumbed to sudden death faster than their Chd4cKO counterparts. In RNA-Seq experiments, we found that cornifin-A was synergistically overexpressed in dKO vs Chd4cKO and that the aberrant expression of this protein increased stiffness and apoptosis of cardiomyocytes, which could explain the observed exacerbated phenotype. Moreover, this overexpression was, at least in part, due to the concomitant downregulation of the micro-RNA miR-150-5p. Thus, our data provide paramount mechanistic evidence for a direct control of heart homeostasis in adult hearts by the Chd4/NuRD chromatin-remodeling complex in cooperation with the transcription factor Zbtb7b.