Control of endothelial cell function and arteriogenesis by MEG3:EZH2 epigenetic regulation of integrin expression.

Autor:	Dunn-Davies H; Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building Max Born Crescent, King's Buildings, Edinburgh EH9 3BF, UK., Dudnakova T; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Nogara A; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Rodor J; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Thomas AC; Bristol Medical School, Translational Health Sciences, University of Bristol, Research and Teaching Floor Level 7, Queens Building, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Parish E; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Gautier P; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK., Meynert A; MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, The University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK., Ulitsky I; Department of Immunology and Regenerative Biology and Department of Molecular Neuroscience, Weizmann-UK Building rm. 007, Weizmann Institute of Science Rehovot 76100, Israel., Madeddu P; Bristol Medical School, Translational Health Sciences, University of Bristol, Research and Teaching Floor Level 7, Queens Building, Bristol Royal Infirmary, Bristol BS2 8HW, UK., Caporali A; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Baker A; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK., Tollervey D; Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building Max Born Crescent, King's Buildings, Edinburgh EH9 3BF, UK., Mitić T; University/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute (QMRI), The University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Apr 06; Vol. 35 (2), pp. 102173. Date of Electronic Publication: 2024 Apr 06 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102173
Abstrakt:	Epigenetic processes involving long non-coding RNAs regulate endothelial gene expression. However, the underlying regulatory mechanisms causing endothelial dysfunction remain to be elucidated. Enhancer of zeste homolog 2 (EZH2) is an important rheostat of histone H3K27 trimethylation (H3K27me3) that represses endothelial targets, but EZH2 RNA binding capacity and EZH2:RNA functional interactions have not been explored in post-ischemic angiogenesis. We used formaldehyde/UV-assisted crosslinking ligation and sequencing of hybrids and identified a new role for maternally expressed gene 3 (MEG3). MEG3 formed the predominant RNA:RNA hybrid structures in endothelial cells. Moreover, MEG3:EZH2 assists recruitment onto chromatin. By EZH2-chromatin immunoprecipitation, following MEG3 depletion, we demonstrated that MEG3 controls recruitment of EZH2/H3K27me3 onto integrin subunit alpha4 ( ITGA4 ) promoter. Both MEG3 knockdown or EZH2 inhibition (A-395) promoted ITGA4 expression and improved endothelial cell migration and adhesion to fibronectin in vitro . The A-395 inhibitor re-directed MEG3 -assisted chromatin remodeling, offering a direct therapeutic benefit by increasing endothelial function and resilience. This approach subsequently increased the expression of ITGA4 in arterioles following ischemic injury in mice, thus promoting arteriogenesis. Our findings show a context-specific role for MEG3 in guiding EZH2 to repress ITGA4 . Novel therapeutic strategies could antagonize MEG3:EZH2 interaction for pre-clinical studies. Competing Interests: The authors declare no competing interests. (© 2024.)
Databáze:	MEDLINE
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