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DNA methylation is associated with altered gene expression in AMD.

Abstract：

PURPOSE:Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Evidence suggests oxidative stress plays a role in the disease. To assess the potential contribution of epigenetic regulation of antioxidant genes relevant to AMD pathogenesis, we evaluated DNA methylation, a tissue-specific genetic modulation that affects gene expression. METHODS:Using the Infinium HumanMethylation27 Illumina platform, we performed DNA bisulfite sequencing to compare the methylation status in postmortem retina pigment epithelium (RPE)/choroid between patients with AMD and age-matched controls. Gene expression was assessed with the Affymetrix Exon Array. TaqMan gene expression assays were used for relative quantification (RT-PCR) confirmation of the expression array results: Glutathione S-transferase isoform mu1 (GSTM1) and mu5 (GSTM5) promoter methylation was confirmed by CpG island bisulfite pyrosequencing. To assess protein levels and localization, we used Western analysis, immunohistochemistry, and immunofluorescence with murine and human samples. RESULTS:The mRNA levels of GSTM1 and GSTM5 were significantly reduced in AMD versus age-matched controls in RPE/choroid and neurosensory retina (NSR), which corresponded to hypermethylation of the GSTM1 promoter. mRNA and protein levels were decreased (RPE to a greater extent than NSR) in AMD postmortem samples, irrespective of age. Immunohistochemistry and immunofluorescence confirm the presence of the enzymes in the NSR and RPE. CONCLUSIONS:Comparison of DNA methylation, together with mRNA levels, revealed significant differences between AMD versus normal retinas. The evidence presented suggests that GSTM1 and GSTM5 undergo epigenetic repression in AMD RPE/choroid, which may increase susceptibility to oxidative stress in AMD retinas.

journal_name

Invest Ophthalmol Vis Sci

journal_title

Investigative ophthalmology & visual science

authors

Hunter A,Spechler PA,Cwanger A,Song Y,Zhang Z,Ying GS,Hunter AK,Dezoeten E,Dunaief JL

doi

10.1167/iovs.11-8449

subject

Has Abstract

pub_date

2012-04-24 00:00:00

pages

2089-105

issue

eissn

0146-0404

issn

1552-5783

pii

iovs.11-8449

journal_volume

pub_type

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DNA methylation is associated with altered gene expression in AMD.