DNA hypermethylation-mediated downregulation of antioxidant genes contributes to the early onset of cataracts in highly myopic eyes
| العنوان: | DNA hypermethylation-mediated downregulation of antioxidant genes contributes to the early onset of cataracts in highly myopic eyes |
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| المؤلفون: | Wenwen He, Xiangjia Zhu, Dan Li, Yu Du, Yi Lu |
| المصدر: | Redox Biology, Vol 19, Iss, Pp 179-189 (2018) Redox Biology |
| بيانات النشر: | Elsevier, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, GSTP1, glutathione S- transferase pi 1, 0301 basic medicine, genetic structures, LEC, lens epithelial cell, Clinical Biochemistry, HMC, highly myopic cataract, medicine.disease_cause, Biochemistry, T-AOC, total antioxidant capacity, 0302 clinical medicine, TXNRD2, High myopia, 5-Aza, 5-Aza-2′-deoxycytidine, Myopia, Promoter Regions, Genetic, lcsh:QH301-705.5, DNMT1, DNA methyl transferase 1, Gene knockdown, lcsh:R5-920, DNA methylation, Chemistry, ARNC, age-related nuclear cataract, Age Factors, Methylation, Middle Aged, CpG site, Female, lcsh:Medicine (General), Research Paper, TXNRD2, thioredoxin reductase 2, OE, overexpress, ABTS, 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), Thioredoxin Reductase 2, TBA, thiobarbituric acid, Cataract, Cell Line, 03 medical and health sciences, Downregulation and upregulation, medicine, Animals, Humans, GSTP1, Aged, KD, knockdown, MDA, malondialdehyde, ARC, age-related cataract, Organic Chemistry, Promoter, Molecular biology, eye diseases, Mice, Inbred C57BL, Oxidative Stress, 030104 developmental biology, Glutathione S-Transferase pi, lcsh:Biology (General), 030221 ophthalmology & optometry, DNMT1, sense organs, CCK-8, cell counting kit 8, Oxidative stress |
| الوصف: | High myopia is recognized as a risk factor for earlier onset of nuclear cataracts. One possible explanation for this is that lenses in highly myopic eyes are exposed to higher levels of oxygen than normal eyes owing to earlier vitreous liquefaction and, hence, are subjected to oxidative insults. Here, we first compared the methylation levels of six essential antioxidant genes (GSTP1, NRF2, OGG1, TXN, TXNRD1 and TXNRD2) between highly myopic cataract (HMC) and age-related cataract (ARC) lens epithelial samples via Sequenom MassARRAY. We found that specific CpG units in the promoters of GSTP1 and TXNRD2 were hypermethylated and that the expression levels of these two genes were lower in the HMC group than in the ARC group. A luciferase reporter assay confirmed the significance of differentially methylated fragments in the activation of transcription. The importance of GSTP1 and TXNRD2 in antioxidant capacity was confirmed by overexpression or knockdown experiments on cultured lens epithelial cells (LECs). In addition, the expression of DNA methyl transferase 1 (DNMT1) was higher in the lens epithelium of HMC patients than that of ARC patients, and the expression of GSTP1 and TXNRD2 was upregulated by use of a DNMT inhibitor in cultured LECs. Finally, we mimicked the intraocular environment of highly myopic eyes by treating LECs with hydrogen peroxide (H2O2) and observed both alterations in the methylation status of the GSTP1 and TXNRD2 promoters and time-dependent altered expression levels. Therefore, we propose that in an environment with high oxygen, in which lenses in highly myopic eyes are immersed, there exists a vicious cycle composed of increased oxidative stress and decreased enzymatic antioxidants via the hypermethylation of antioxidant genes. Graphical abstract fx1 Highlights • Vitreous liquefaction generates a high-O2 environment surrounding the lens. • In highly myopic eyes, vitreous liquefaction occurs earlier and results in severer nuclear cataract. • Methylation levels of GSTP1 and TXNRD2 were elevated in lens epithelium of highly myopic eyes. • Increased oxidation and decreased enzymatic antioxidant via hypermethylation form a vicious circle in highly myopic eyes. |
| اللغة: | English |
| تدمد: | 2213-2317 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::05f807e12a3efb225e7a37e033f7b247Test http://www.sciencedirect.com/science/article/pii/S2213231718304750Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....05f807e12a3efb225e7a37e033f7b247 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22132317 |
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