Effect of diabetes status and hyperglycemia on global DNA methylation and hydroxymethylation.
Effect of diabetes status and hyperglycemia on global DNA methylation and hydroxymethylation.
复制标题
DOI：
10.1530/ec-17-0199
复制
发表时间：
2017-11
影响因子：
2.9
通讯作者：
López-Segura V
中科院分区：
文献类型：
--
作者：
Pinzón-Cortés JA;Perna-Chaux A;Rojas-Villamizar NS;Díaz-Basabe A;Polanía-Villanueva DC;Jácome MF;Mendivil CO;Groot H;López-Segura V
2型糖尿病（T2 DM）的特征是氧化应激，可导致慢性微血管和大血管并发症。我们假设，一些靶器官损伤是由涉及DNA甲基化（5 mC）和DNA羟甲基化（5 hmC）的表观遗传机制中的氧化改变介导的。我们分析了控制良好和控制不佳的T2 DM患者外周血细胞的总体DNA甲基化和羟甲基化，并将其与健康对照组进行比较。我们还分析了GEO数据库中糖尿病背景下其他重要组织的DNA甲基化和基因表达的微阵列，然后将这些结果与我们的实验基因表达数据进行比较。与控制良好和健康的个体相比，控制不良的患者的DNA甲基化，更重要的是DNA羟甲基化水平增加。5 mC和5 hmC测量值均与糖化血红蛋白的百分比相关，表明高血糖症对表观基因组变化的直接影响。甲基化微阵列分析结果一致，T2 DM患者外周血中5 mC水平升高。然而，DNA甲基化水平与其他组织（如胰腺、脂肪组织和骨骼肌）相反。我们假设与高血糖相关的DNA氧化过程可以解释DNA去甲基化，其中10 - 11易位（泰特）蛋白的活性不足以完成该过程。高水平的葡萄糖导致细胞氧化，其触发由泰特酶辅助的DNA去甲基化过程，导致受损组织的表观遗传失调。
Type 2 diabetes mellitus (T2DM) is characterized by oxidative stress that could lead to chronic micro- and macrovascular complications. We hypothesized that some of the target organ damage is mediated by oxidative alterations in epigenetic mechanisms involving DNA methylation (5mC) and DNA hydroxymethylation (5hmC). We analyzed global DNA methylation and hydroxymethylation in peripheral blood cells in well-controlled and poorly controlled patients with T2DM and compared them with healthy controls. We also analyzed microarrays of DNA methylation and gene expression of other important tissues in the context of diabetes from the GEO database repository and then compared these results with our experimental gene expression data. DNA methylation and, more importantly, DNA hydroxymethylation levels were increased in poorly controlled patients compared to well-controlled and healthy individuals. Both 5mC and 5hmC measurements were correlated with the percentage of glycated hemoglobin, indicating a direct impact of hyperglycemia on changes over the epigenome. The analysis of methylation microarrays was concordant, and 5mC levels were increased in the peripheral blood of T2DM patients. However, the DNA methylation levels were the opposite of those in other tissues, such as the pancreas, adipose tissue and skeletal muscle. We hypothesize that a process of DNA oxidation associated with hyperglycemia may explain the DNA demethylation in which the activity of ten-eleven translocation (TET) proteins is not sufficient to complete the process. High levels of glucose lead to cellular oxidation, which triggers the process of DNA demethylation aided by TET enzymes, resulting in epigenetic dysregulation of the damaged tissues.