Enhancer of Zeste Homolog 2 (EZH2) Contributes to Rod Photoreceptor Death Process in Several Forms of Retinal Degeneration and Its Activity Can Serve as a Biomarker for Therapy Efficacy.

Détails

ID Serval
serval:BIB_CD3CAE19D3B7
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Enhancer of Zeste Homolog 2 (EZH2) Contributes to Rod Photoreceptor Death Process in Several Forms of Retinal Degeneration and Its Activity Can Serve as a Biomarker for Therapy Efficacy.
Périodique
International journal of molecular sciences
Auteur⸱e⸱s
Mbefo M., Berger A., Schouwey K., Gérard X., Kostic C., Beryozkin A., Sharon D., Dolfuss H., Munier F., Tran H.V., van Lohuizen M., Beltran W.A., Arsenijevic Y.
ISSN
1422-0067 (Electronic)
ISSN-L
1422-0067
Statut éditorial
Publié
Date de publication
28/08/2021
Peer-reviewed
Oui
Volume
22
Numéro
17
Pages
9331
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Résumé
Inherited retinal dystrophies (IRD) are due to various gene mutations. Each mutated gene instigates a specific cell homeostasis disruption, leading to a modification in gene expression and retinal degeneration. We previously demonstrated that the polycomb-repressive complex-1 (PRC1) markedly contributes to the cell death process. To better understand these mechanisms, we herein study the role of PRC2, specifically EZH2, which often initiates the gene inhibition by PRC1. We observed that the epigenetic mark H3K27me3 generated by EZH2 was progressively and strongly expressed in some individual photoreceptors and that the H3K27me3-positive cell number increased before cell death. H3K27me3 accumulation occurs between early (accumulation of cGMP) and late (CDK4 expression) events of retinal degeneration. EZH2 hyperactivity was observed in four recessive and two dominant mouse models of retinal degeneration, as well as two dog models and one IRD patient. Acute pharmacological EZH2 inhibition by intravitreal injection decreased the appearance of H3K27me3 marks and the number of TUNEL-positive cells revealing that EZH2 contributes to the cell death process. Finally, we observed that the absence of the H3K27me3 mark is a biomarker of gene therapy treatment efficacy in XLRPA2 dog model. PRC2 and PRC1 are therefore important actors in the degenerative process of multiple forms of IRD.
Mots-clé
Animals, DNA Methylation, Dogs, Enhancer of Zeste Homolog 2 Protein/genetics, Enhancer of Zeste Homolog 2 Protein/metabolism, Epigenesis, Genetic, Eye Proteins/physiology, Histones/genetics, Histones/metabolism, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Polycomb Repressive Complex 1/physiology, Proto-Oncogene Proteins/physiology, Retinal Degeneration/etiology, Retinal Degeneration/metabolism, Retinal Degeneration/pathology, Retinal Rod Photoreceptor Cells/metabolism, Retinal Rod Photoreceptor Cells/pathology, Retinitis Pigmentosa/etiology, Retinitis Pigmentosa/metabolism, Retinitis Pigmentosa/pathology, epigenetic, neuroprotection, polycomb-repressive complex, retinal degeneration
Pubmed
Web of science
Open Access
Oui
Création de la notice
21/09/2021 14:03
Dernière modification de la notice
05/01/2022 7:36
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