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Z. Smit-McBride, L. M. Hjelmeland; Age and Gender Dependent Differential Promoter Methylation of Oxidative Stress Response Genes in the Mouse RPE/Choroid. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1691.
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© ARVO (1962-2015); The Authors (2016-present)
Promoter methylation has been shown to have a profound regulatory effect on gene expression in cancer biology. We hypothesize that alteration of promoter methylation plays a key role in the regulation of gene expression in aging and age-related disease. The current study evaluates gender and age differences in the promoter methylation of several oxidative stress genes in the mouse RPE/choroid.
C57BL/6J mice (male and female) at 6 weeks and 18 months of age were obtained from the Jackson Laboratory and the NIA, respectively. The RPE/choroid was dissected after which genomic DNA was isolated. The DNA was used for comparative genomic hybridization to determine the methylation status of a large set of mouse gene promoters on Affymetrix Mouse Promoter 1.0 R Tiling Arrays. Data were analyzed using the Affymetrix TAS software, the Galaxy browser from Penn State and GeneSpring GX 11.
We chose a group of genes related to the oxidative stress response to first quantify age-related changes in promoter methylation: Sod2, Prdx3, Txn2, Esr1, Esrrα, Foxo3a, Nfe2l2 (Nrf2), Ppargc1a (Pgc1) , Sirt1, Shc1, Txnrd2, and Ywhaq (14-3-3 theta) . At a significance level of p< 0.05, we found age-depended differential promoter methylation among the males and females, as well as gender-dependent differential methylation among the young and old mice in a gene-specific fashion. For the Sod2 promoter we observed a loss of intron 2 methylation in old males and an increase of promoter/exon I methylation in old females. Sod2, Foxo3a, Nrf2, Sirt1 all have age-dependent differential promoter methylation among the males and females. Erα, Prdx3, 14-3-3 and Txn2 have none. Pgc1 exhibits a loss of methylation with age. The Errα gene exhibits the same region methylated in old males and females.
We found gender-dependent and age-dependent differential methylation for several but not all genes. Further studies correlating methylation changes with expression changes are in progress, and pursuit of functional role of these changes in aging is needed. Methylation analysis of these gene promoters by bisulfite sequencing is currently being performed.
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