EZH2型
癌症研究
视网膜
生物
组蛋白H3
视网膜变性
视网膜
细胞生物学
组蛋白
基因敲除
癌症
色素性视网膜炎
视网膜色素上皮
作者
Martial Mbefo,Adeline Berger,Karine Schouwey,Xavier Gérard,Corinne Kostic,Avigail Beryozkin,Dror Sharon,Hélène Dolfuss,Francis L. Munier,Hoai Viet Tran,Maarten van Lohuizen,William A. Beltran,Yvan Arsenijevic
摘要
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.
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