# Endothelial RNF20 suppresses endothelial-to-mesenchymal transition and safeguards physiological angiocrine signaling to prevent congenital heart disease

## TL;DR

RNF20 helps heart development by preventing endothelial cells from turning into mesenchymal cells and maintaining proper signaling.

## Contribution

The study reveals RNF20's novel role in regulating TGF-β signaling and Nrg1 expression in cardiac endothelial cells.

## Key findings

- RNF20 restrains TGF-β signaling by affecting RNA polymerase II pause release in endothelial cells.
- Loss of RNF20 leads to endothelial-to-mesenchymal transition and impaired heart development.
- Reduced RNF20 in patient endothelial cells correlates with TGF-β signaling and heart disease severity.

## Abstract

Heart morphogenesis 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 key functions of the histone H2B ubiquitin (H2Bub1) ligase RNF20 in second heart field development and cardiac endothelial cells. We demonstrate that RNF20 promotes Nrg1 expression through a RNF20-H2Bub1-dependent mechanism and restrains TGF-β signaling by influencing RNA polymerase II pause release at TGF-β target genes in endothelial cells. While heightened TGF-β signaling following RNF20 loss results endothelial-to-mesenchymal transition (EndMT), both impaired Nrg1 signaling and elevated TGF-β activity contribute to abnormal cardiomyocyte proliferation and contractility. 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 crucial role for RNF20 in safeguarding endothelial identity and physiological angiocrine signaling, thereby ensuring proper heart development and function.

Heart development and function rely on communication among diverse cardiac cells. Here, the authors show that RNF20 safeguards endothelial cell identity and orchestrates heart morphogenesis and contractility by restraining TGF-β signaling and modulating angiocrine communication.