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

Yanliang Dou, Nalan Tetik-Elsherbiny, Rui Gao, Yonggang Ren, Yu-wen Chen, Moritz Merbecks, Aadhyaa Setya, Olga Lityagina, Yinuo Wang, Evgeny Chichelnitskiy, Aya Abouissa, Chi-Chung Wu, Guillermo Barreto, Michael Potente, Thomas Wieland, Roxana Ola, Philippe Grieshaber, Tsvetomir Loukanov, Matthias Gorenflo, Joerg Heineke, Julio Cordero () and Gergana Dobreva ()
Additional contact information
Yanliang Dou: Heidelberg University
Nalan Tetik-Elsherbiny: Heidelberg University
Rui Gao: Heidelberg University
Yonggang Ren: Heidelberg University
Yu-wen Chen: Heidelberg University
Moritz Merbecks: University Hospital Heidelberg
Aadhyaa Setya: Heidelberg University
Olga Lityagina: Heidelberg University
Yinuo Wang: Heidelberg University
Evgeny Chichelnitskiy: Max Planck Institute for Heart and Lung Research
Aya Abouissa: Heidelberg University
Chi-Chung Wu: Heidelberg University
Guillermo Barreto: Laboratoire IMoPA
Michael Potente: Berlin Institute of Health at Charité—Universitätsmedizin Berlin
Thomas Wieland: German Centre for Cardiovascular Research (DZHK)
Roxana Ola: Heidelberg University
Philippe Grieshaber: University Hospital Heidelberg
Tsvetomir Loukanov: University Hospital Heidelberg
Matthias Gorenflo: University Hospital Heidelberg
Joerg Heineke: Heidelberg University
Julio Cordero: Heidelberg University
Gergana Dobreva: Heidelberg University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-65291-0

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