Endothelial RNF20 Suppresses Endothelial-to-Mesenchymal Transition and Safeguards Physiological Angiocrine Signaling to Prevent Congenital Heart Disease [Bulk_polyA RNA-seq]

Heart development and function rely on intricate communication among distinct cardiac cell types. How their co-development and crosstalk are coordinated is largely unexplored. Our study unveils novel functions of the histone H2B ubiquitin (H2Bub1) ligase RNF20 in second heart field development and cardiac endothelial cells, essential for proper cardiac morphogenesis and function. We demonstrate that RNF20-H2Bub1-dependent reduction in Nrg1 expression, coupled with heightened TGF-β signaling due to RNF20's role in inducing RNA polymerase II pausing at TGF-β targets, drives increased endothelial-to-mesenchymal transition (EndMT), abnormal cardiomyocyte proliferation, and irregular contractility upon endothelial RNF20 loss. Importantly, RNF20 expression is significantly reduced in cardiac endothelial cells from congenital heart disease patients showing a positive correlation with oxygen saturation and a negative correlation with key components and downstream effectors of TGF-β signaling. In summary, our work identifies a novel role of RNF20 in controlling signaling inputs that safeguard physiological angiocrine signaling ensuring proper cardiac morphogenesis and function.