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
| Autor: | Yvan Arsenijevic, Maarten van Lohuizen, Dror Sharon, Francis L. Munier, Karine Schouwey, Adeline Berger, Martial Mbefo, Corinne Kostic, William A. Beltran, Hélène Dolfuss, Avigail Beryozkin, Xavier Gérard, Hoai Viet Tran |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Retinal degeneration
Programmed cell death QH301-705.5 Genetic enhancement macromolecular substances Biology Gene mutation 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 Catalysis Article Inorganic Chemistry Histones Retinal Rod Photoreceptor Cells Proto-Oncogene Proteins Gene expression medicine Enhancer of Zeste Homolog 2 Protein Physical and Theoretical Chemistry Biology (General) Eye Proteins Molecular Biology QD1-999 Spectroscopy Polycomb Repressive Complex 1 Organic Chemistry EZH2 General Medicine medicine.disease Computer Science Applications Cell biology Chemistry Cell Death Process Retinal Dystrophies Retinitis Pigmentosa |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 9331, p 9331 (2021) International Journal of Molecular Sciences Volume 22 Issue 17 International journal of molecular sciences, vol. 22, no. 17, pp. 9331 |
| ISSN: | 1661-6596 1422-0067 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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