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

Dou, Yanliang; Tetik-Elsherbiny, Nalan; Gao, Rui; Ren, Yonggang; Chen, Yu-Wen; Merbecks, Moritz; Setya, Aadhyaa; Lityagina, Olga; Wang, Yinuo; Chichelnitskiy, Evgeny; Abouissa, Aya; Wu, Chi-Chung; Barreto, Guillermo; Potente, Michael; Wieland, Thomas; Ola, Roxana; Grieshaber, Philippe; Loukanov, Tsvetomir; Gorenflo, Matthias; Heineke, Joerg; Cordero, Julio; Dobreva, Gergana

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

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Item Type:	Article
Title:	Endothelial RNF20 suppresses endothelial-to-mesenchymal transition and safeguards physiological angiocrine signaling to prevent congenital heart disease
Creators Name:	Dou, Yanliang, Tetik-Elsherbiny, Nalan, Gao, Rui, Ren, Yonggang, Chen, Yu-Wen, Merbecks, Moritz, Setya, Aadhyaa, Lityagina, Olga, Wang, Yinuo, Chichelnitskiy, Evgeny, Abouissa, Aya, Wu, Chi-Chung, Barreto, Guillermo, Potente, Michael, Wieland, Thomas, Ola, Roxana, Grieshaber, Philippe, Loukanov, Tsvetomir, Gorenflo, Matthias, Heineke, Joerg, Cordero, Julio and Dobreva, Gergana
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.
Keywords:	Cardiac Myocytes, Cell Proliferation, Congenital Heart Defects, Endothelial Cells, Epithelial-Mesenchymal Transition, Heart, Signal Transduction, Transforming Growth Factor Beta, Ubiquitin-Protein Ligases, Animals, Mice
Source:	Nature Communications
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Volume:	16
Number:	1
Page Range:	9480
Date:	27 October 2025
Official Publication:	https://doi.org/10.1038/s41467-025-65291-0
PubMed:	View item in PubMed
Related to:	URL URL Type https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE246928 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305562 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE212524 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE203274 External Dataset https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE108963 External Dataset https://github.com/jcorderJC12/03Rnf20_CHD_NatC Software

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