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首页> 外文期刊>Redox Biology >DNA hypermethylation-mediated downregulation of antioxidant genes contributes to the early onset of cataracts in highly myopic eyes
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DNA hypermethylation-mediated downregulation of antioxidant genes contributes to the early onset of cataracts in highly myopic eyes

机译：DNA高甲基化介导的抗氧化基因下调有助于高度近视眼白内障的早期发作

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摘要

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.
机译：高度近视被认为是核性白内障较早发作的危险因素。对此的一种可能解释是，由于较早的玻璃液化作用，高度近视眼的镜片比正常眼暴露于更高水平的氧气，因此遭受了氧化损伤。在这里，我们首先通过Sequenom MassARRAY比较了高度近视性白内障（HMC）和年龄相关性白内障（ARC）晶状体上皮样本中六个必需抗氧化剂基因（GSTP1，NRF2，OGG1，TXN，TXNRD1和TXNRD2）的甲基化水平。我们发现，GSTP1和TXNRD2启动子中的特定CpG单元被高度甲基化，并且HMC组中这两个基因的表达水平低于ARC组。荧光素酶报告基因测定证实了差异甲基化片段在转录激活中的重要性。 GSTP1和TXNRD2在抗氧化能力中的重要性已通过在培养的晶状体上皮细胞（LEC）上的过表达或敲除实验得到证实。此外，HMC患者晶状体上皮中的DNA甲基转移酶1（DNMT1）的表达高于ARC患者，并且在培养的LEC中使用DNMT抑制剂可上调GSTP1和TXNRD2的表达。最后，我们通过用过氧化氢（H 2 O 2 ）处理LEC来模拟高度近视眼的眼内环境，并观察到GSTP1和TXNRD2的甲基化状态均发生了变化启动子和时间依赖性改变的表达水平。因此，我们提出，在高氧环境中，高度近视眼的镜片浸入其中，存在一个恶性循环，该恶性循环由抗氧化基因的超甲基化导致氧化应激增加和酶促抗氧化剂减少。

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