Abstract
Original language | English |
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Article number | 4461 |
Journal | Nature communications |
Volume | 14 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2023 |
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In: Nature communications, Vol. 14, No. 1, 4461, 01.12.2023.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI
AU - Rondeaux, Julie
AU - Groussard, D. borah
AU - Renet, Sylvanie
AU - Tardif, Virginie
AU - Dumesnil, Anaïs
AU - Chu, Alphonse
AU - di Maria, L. a
AU - Lemarcis, Théo
AU - Valet, Manon
AU - Henry, Jean-Paul
AU - Badji, Zina
AU - Vézier, Claire
AU - Béziau-Gasnier, Delphine
AU - Neele, Annette E.
AU - de Winther, Menno P. J.
AU - Guerrot, Dominique
AU - Brand, Marjorie
AU - Richard, Vincent
AU - Durand, Eric
AU - Brakenhielm, Ebba
AU - Fraineau, Sylvain
N1 - Funding Information: We thank all physicians from the department of cardiology (Rouen University Hospital) for their help in the collection of peripheral blood samples from patients; Nicolas Perzo, Dr. Thomas Duflot, and Pr. Jérémy Bellien for critical commenting on experiments and Gaëtan Riou from CyFlow flow cytometry and cell analysis facility platform (Institute for Research and Innovation in Biomedicine, IRIB) for his help in performing flow cytometry experiments and analysis. We thank the ENCODE Consortium and the Bradley Bernstein, Broad Institute of MIT and Harvard ENCODE production laboratory for generating the GSE29611 ChIP-seq data sets, and more particularly for generating respectively GSM1003536 and GSM1003564 human CD14+monocytes H3K4me3 and H3K27me3 ChIP-seq data sets. Professors E.D. (MD-PhD), V.R. (MD-PhD), D.G. (MD-PhD); Doctors J.R. (PhD), D.G. (PhD), V.T. (PhD), D.B.G. (PhD), E.B. (PhD), S.F. (PhD); Mrs S.R. (BsC), A.D. (BsC), L.D.M. (MsC), M.V. (BsC), Z.B. (BsC), C.V. (MsC) and Mr T.L. (MsC), J.P.H. (BsC) are all part of the University Hospital Federations CArdiac Research Network on Aortic VAlve and heart faiLure (FHU CARNAVAL) consortium for which a GCS G4 grant is granted. This study was supported with grants from the University of Rouen Normandy, the GCS G4 FHU Early Markers of Cardiovascular Remodeling in Valvulopathy and Heart Failure (FHU REMOD-VHF) and FHU CARNAVAL as well as generalized institutional funds (INSERM U1096 EnVI laboratory) from French National Institute of Health and Medical Research (INSERM) and the Normandy Region together with the European Union. Julie Rondeaux is co-supported by a fellowship from European Union and Région Normandie. Europe gets involved in Normandie with European Regional Development Fund (ERDF): CPER/FEDER 2015 (DO-IT) and CPER/FEDER 2016 (PACT-CBS). This project required the use of equipment acquired by the Hospital-University Research in Health project Search Treatment and improve Outcome for Patients with Aortic Stenosis (RHU STOP-AS) supported by the French Government and managed by the National Research Agency (ANR) under the program “Investissements d’avenir” with the reference ANR-16-RHUS-0003. Figure S17 was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license. Funding Information: We thank all physicians from the department of cardiology (Rouen University Hospital) for their help in the collection of peripheral blood samples from patients; Nicolas Perzo, Dr. Thomas Duflot, and Pr. Jérémy Bellien for critical commenting on experiments and Gaëtan Riou from CyFlow flow cytometry and cell analysis facility platform (Institute for Research and Innovation in Biomedicine, IRIB) for his help in performing flow cytometry experiments and analysis. We thank the ENCODE Consortium and the Bradley Bernstein, Broad Institute of MIT and Harvard ENCODE production laboratory for generating the GSE29611 ChIP-seq data sets, and more particularly for generating respectively GSM1003536 and GSM1003564 human CD14+monocytes H3K4me3 and H3K27me3 ChIP-seq data sets. Professors E.D. (MD-PhD), V.R. (MD-PhD), D.G. (MD-PhD); Doctors J.R. (PhD), D.G. (PhD), V.T. (PhD), D.B.G. (PhD), E.B. (PhD), S.F. (PhD); Mrs S.R. (BsC), A.D. (BsC), L.D.M. (MsC), M.V. (BsC), Z.B. (BsC), C.V. (MsC) and Mr T.L. (MsC), J.P.H. (BsC) are all part of the University Hospital Federations CArdiac Research Network on Aortic VAlve and heart faiLure (FHU CARNAVAL) consortium for which a GCS G4 grant is granted. This study was supported with grants from the University of Rouen Normandy, the GCS G4 FHU Early Markers of Cardiovascular Remodeling in Valvulopathy and Heart Failure (FHU REMOD-VHF) and FHU CARNAVAL as well as generalized institutional funds (INSERM U1096 EnVI laboratory) from French National Institute of Health and Medical Research (INSERM) and the Normandy Region together with the European Union. Julie Rondeaux is co-supported by a fellowship from European Union and Région Normandie. Europe gets involved in Normandie with European Regional Development Fund (ERDF): CPER/FEDER 2015 (DO-IT) and CPER/FEDER 2016 (PACT-CBS). This project required the use of equipment acquired by the Hospital-University Research in Health project Search Treatment and improve Outcome for Patients with Aortic Stenosis (RHU STOP-AS) supported by the French Government and managed by the National Research Agency (ANR) under the program “Investissements d’avenir” with the reference ANR-16-RHUS-0003. Figure was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license. Publisher Copyright: © 2023, The Author(s).
PY - 2023/12/1
Y1 - 2023/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85165698659&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-023-40186-0
DO - https://doi.org/10.1038/s41467-023-40186-0
M3 - Article
C2 - 37491334
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4461
ER -