Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI

Julie Rondeaux, Déborah Groussard, Sylvanie Renet, Virginie Tardif, Anaïs Dumesnil, Alphonse Chu, Léa Maria, Théo Lemarcis, Manon Valet, Jean-Paul Henry, Zina Badji, Claire Vézier, Delphine Béziau-Gasnier, Annette E. Neele, Menno P. J. Winther, Dominique Guerrot, Marjorie Brand, Vincent Richard, Eric Durand, Ebba Brakenhielm and Sylvain Fraineau ()
Additional contact information
Julie Rondeaux: Inserm EnVI UMR 1096
Déborah Groussard: Inserm EnVI UMR 1096
Sylvanie Renet: Inserm EnVI UMR 1096
Virginie Tardif: Inserm EnVI UMR 1096
Anaïs Dumesnil: Inserm EnVI UMR 1096
Alphonse Chu: Ottawa Hospital Research Institute, General Hospital
Léa Maria: Inserm EnVI UMR 1096
Théo Lemarcis: Inserm EnVI UMR 1096
Manon Valet: Inserm EnVI UMR 1096
Jean-Paul Henry: Inserm EnVI UMR 1096
Zina Badji: CHU Rouen, Department of Cardiology
Claire Vézier: CHU Rouen, Department of Cardiology
Delphine Béziau-Gasnier: CHU Rouen, Department of Cardiology
Annette E. Neele: University of Amsterdam
Menno P. J. Winther: University of Amsterdam
Dominique Guerrot: Univ Rouen Normandie, Inserm EnVI UMR 1096, CHU Rouen, Department of Nephrology
Marjorie Brand: Ottawa Hospital Research Institute, General Hospital
Vincent Richard: Univ Rouen Normandie, Inserm EnVI UMR 1096, CHU Rouen, Department of Pharmacology
Eric Durand: Univ Rouen Normandie, Inserm EnVI UMR 1096, CHU Rouen, Department of Cardiology
Ebba Brakenhielm: Inserm EnVI UMR 1096
Sylvain Fraineau: Inserm EnVI UMR 1096

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to impact cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time an ectopic EZH2, and putative, cytoplasmic inactive localization of the epigenetic enzyme, during monocyte differentiation into M2 macrophages in vitro as well as in immunomodulatory cardiac macrophages in vivo in the post-MI acute inflammatory phase. Moreover, we show that pharmacological EZH2 inhibition, with GSK-343, resolves H3K27 methylation of bivalent gene promoters, thus enhancing their expression to promote human monocyte repair functions. In line with this protective effect, GSK-343 treatment accelerated cardiac inflammatory resolution preventing infarct expansion and subsequent cardiac dysfunction in female mice post-MI in vivo. In conclusion, our study reveals that pharmacological epigenetic modulation of cardiac-infiltrating immune cells may hold promise to limit adverse cardiac remodeling after MI.

Date: 2023
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DOI: 10.1038/s41467-023-40186-0

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