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Xiang-Jia Zhu, Yi Lu; DNA Hypermethylation Mediated Downregulation of Antioxidant Genes in Early Onset of Cataract in High Myopic Eyes. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3035.
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© ARVO (1962-2015); The Authors (2016-present)
To inspect whether antioxidant defense is impaired in high myopic eyes and further investigate the underlying epigenetic etiology of high myopic cataract.
Methylation levels of six essential antioxidant genes (GSTP1; NRF2; OGG1; TXN; TXNRD1 and TXNRD2) in lens epithelium were compared between high myopic cataract group and age-related cataract group via Sequenom MassARRAY. Expression of DNMT1 was also compared. Significance of deferentially methylated fragments in maintenance of promoter activity were verified with luciferase reporter assay. 5-Aza treatment were carried out in lens epithelial cells (LECs). H2O2 treatment of LECs was also performed to mimic the intraocular oxidative environment of high myopic eyes, and methylation changes in GSTP1 and TXNRD2 were investigated.
In high myopic cataract, CpG units in the promoter of GSTP1 and TXNRD2 were hypermethylated comparing to age-related cataract, which was possibly mediated by the elevated DNMT1, and the expressions of these two genes were significantly downregulated. Luciferase reporter assay confirmed the significance of deferentially methylated fragments of these two genes in activation of transcription, and treatment with 5-Aza led to significant increases of GSTP1 and TXNRD2 expressions in LECs. H2O2 treatment also led to hypermethylation of GSTP1 and TXNRD2 genes, followed by down regulation of their mRNA expressions.
GSTP1 and TXNRD2, out of the six screened antioxidant genes of study, were downregulated by the hypermethylation of CpG units in the very proximity of transcription start sites, which evidenced the impaired antioxidant capacity in highly myopic eyes. And by treating LECs with H2O2 to mimic the hyperoxic microenvironment surrounding lens of high myopic eyes, the underlying mechanism of early cataract onset in high myopic eyes was unveiled, revealing a profounder understanding of the interplay between oxidative stress and epigenetic modification.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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