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.

Martial Mbefo,Avigail Beryozkin,Corinne Kostic,Hoai Viet Tran,Francis Munier,Dror Sharon,Adeline Berger,Hélène Dolfuss,Xavier Gérard,Karine Schouwey,Yvan Arsenijevic,William A Beltran,Maarten Van Lohuizen

doi:10.3390/ijms22179331

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.

Highlights

Inherited retinal dystrophies (IRDs) are caused by at least 300 different mutated genes (RetNet Available online: https://sph.uth.edu/retnet/)
We have previously demonstrated that the polycomb-repressive complex-1 (PRC1) has a permissive role for the cell cycle activation during retinal degeneration, but we did not investigate the potential role of PRC2, which often interacts with PRC1
We have previously shown that cell death in Rd1 photoreceptors is tightly dependent on the PRC1-member BMI1 but that its molecular action is independent of the downstream conventional Ink4a/Arf pathway [2]

Summary

Introduction

Inherited retinal dystrophies (IRDs) are caused by at least 300 different mutated genes (RetNet Available online: https://sph.uth.edu/retnet/ (accessed on 27 August 2021)). As examples of rod photoreceptor degeneration, cGMP accumulation was observed in early disease stages of several recessive and dominant animal models of retinitis pigmentosa (RP) [1], while cell cycle reactivation with re-expression of CDK4, for example, occurs at a later degenerative stage [2]. Other common pathways were shown to be activated such as PKG, PARP, Neogenin, microglia activation, Retbindin, etc. We hypothesized that gene regulation changes occurring during the degenerative process could be the common origin of the activation of these pathways. Several groups have shown by transcriptomic analyses that dozens of genes were differently expressed during the degenerative process [8,9,10]. We have previously demonstrated that the polycomb-repressive complex-1 (PRC1) has a permissive role for the cell cycle activation during retinal degeneration, but we did not investigate the potential role of PRC2, which often interacts with PRC1

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