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

Unit of Retinal Degeneration and Regeneration, Department of Ophthalmology, University of Lausanne, Fondation Asile des Aveugles, 1004 Lausanne, Switzerland

Hadassah Medical Center, Faculty of Medicine, The Hebrew University Jerusalem, Jerusalem 91120, Israel

UMR_S 1112, Laboratoire de Génétique Médicales, University of Strasbourg, CEDEX, 67084 Strasbourg, France

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Unit of Oculogenetics, Department of Ophthalmology, University of Lausanne, Fondation Asile des Aveugles, 1004 Lausanne, Switzerland

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Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

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Division of Experimental Retinal Therapies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

Author to whom correspondence should be addressed.

Academic Editor: Jan Wijnholds

Int. J. Mol. Sci. 2021, 22(17), 9331; https://doi.org/10.3390/ijms22179331

Received: 26 July 2021 / Revised: 18 August 2021 / Accepted: 25 August 2021 / Published: 28 August 2021

(This article belongs to the Special Issue Retinal Degeneration: From Pathophysiology to Therapeutic Approaches 3.0)

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Abstract

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. View Full-Text

Keywords: retinal degeneration; polycomb-repressive complex; neuroprotection; epigenetic

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MDPI and ACS Style

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. 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. Int. J. Mol. Sci. 2021, 22, 9331. https://doi.org/10.3390/ijms22179331

AMA Style

Mbefo M, Berger A, Schouwey K, Gérard X, Kostic C, Beryozkin A, Sharon D, Dolfuss H, Munier F, Tran HV, van Lohuizen M, Beltran WA, Arsenijevic Y. 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. International Journal of Molecular Sciences. 2021; 22(17):9331. https://doi.org/10.3390/ijms22179331

Chicago/Turabian Style

Mbefo, Martial, Adeline Berger, Karine Schouwey, Xavier Gérard, Corinne Kostic, Avigail Beryozkin, Dror Sharon, Hélène Dolfuss, Francis Munier, Hoai Viet Tran, Maarten van Lohuizen, William A. Beltran, and Yvan Arsenijevic. 2021. "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" International Journal of Molecular Sciences 22, no. 17: 9331. https://doi.org/10.3390/ijms22179331

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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

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