Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 17, Pages -Publisher
MDPI
DOI: 10.3390/ijms22179331
Keywords
retinal degeneration; polycomb-repressive complex; neuroprotection; epigenetic
Funding
- Swiss National Foundation [32ER30_1187383]
- Provisu Foundation
- Innosuisse [44271.1 IP-LS]
- National Eye Institute [R01 EY006855, EY017549, P30-EY001583]
- Foundation Fighting Blindness
- Van Sloun Fund for Canine Genetic Research
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This research investigates the important roles of PRC1 and PRC2 in the degenerative process of multiple forms of IRD, revealing that the hyperactivity of EZH2 is closely associated with cell death processes and the absence of the H3K27me3 mark can serve as a biomarker for gene therapy treatment efficacy.
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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