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首页> 外文期刊>Journal of applied toxicology >The effect of a methyl-deficient diet on the global DNA methylation and the DNA methylation regulatory pathways
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The effect of a methyl-deficient diet on the global DNA methylation and the DNA methylation regulatory pathways

机译：甲基缺陷饮食对全球DNA甲基化和DNA甲基化调节途径的影响

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Methyl-deficient diets are known to induce various liver disorders, in which DNA methylation changes are implicated. Recent studies have clarified the existence of the active DNA demethylation pathways that start with oxidization of 5-methylcytosine (5meC) to 5-hydroxymethylcytosine by ten-eleven translocation (Tet) enzymes, followed by the action of base-excision-repair pathways. Here, we investigated the effects of a methionine-choline-deficient (MCD) diet on the hepatic DNA methylation of mice by precisely quantifying 5meC using a liquid chromatography-electrospray ionization-mass spectrometry and by investigating the regulatory pathways, including DNA demethylation. Although feeding the MCD diet for 1 week induced hepatic steatosis and lower level of the methyl donor S-adenosylmethionine, it did not cause a significant reduction in the 5meC content. On the other hand, the MCD diet significantly upregulated the gene expression of the Tet enzymes, Tet2 and Tet3, and the base-excision-repair enzymes, thymine DNA glycosylase and apurinic/apyrimidinic-endonuclease 1. At the same time, the gene expression of DNA methyltransferase 1 and a, was also significantly increased by the MCD diet. These results suggest that the DNA methylation level is precisely regulated even when dietary methyl donors are restricted. Methyl-deficient diets are well known to induce oxidative stress and the oxidative-stress-induced DNA damage, 8-hydroxy-2-deoxyguanosine (8OHdG), is reported to inhibit DNA methylation. In this study, we also clarified that the increase in 8OHdG number per DNA by the MCD diet is approximately 10 000 times smaller than the reduction in 5meC number, suggesting the contribution of 8OHdG formation to DNA methylation would not be significant. Copyright (c) 2015 John Wiley & Sons, Ltd.
机译：已知缺乏饮食诱导各种肝病，其中DNA甲基化变化是牵连的。最近的研究已经阐明了活性DNA去甲基化途径，其通过10-11-100级易位（TET）酶的氧化氧化以5-甲基胞嘧啶（5MMEC）至5-羟甲基胞嘧啶，其次是碱 - 切除修复途径的作用。在这里，我们通过使用液相色谱 - 电喷雾电离质谱法精确定量5MEC并通过研究调节途径，研究了甲硫氨酸 - 胆碱缺陷（MCD）饮食对小鼠的肝脏DNA甲基化的影响，包括DNA去甲基化。虽然喂养MCD饮食1周诱导的肝脏脂肪变性和甲基供体S-腺苷甲基硫甲硫醚的较低水平，但它不会导致5MEC含量显着降低。另一方面，MCD饮食显着上调了TET酶，TET2和TET3的基因表达，以及基氨切除修复酶，胸腺嘧啶DNA糖基酶和膜膜 - 内切核酸酶1。同时，基因表达通过MCD饮食也显着增加DNA甲基转移酶1和A.这些结果表明，即使限制膳食甲基供体，也会精确调节DNA甲基化水平。据报道，甲基缺乏饮食众所周知促使氧化应激和氧化应激诱导的DNA损伤，8-羟基-2-脱氧核苷酸（8Ohdg）抑制DNA甲基化。在这项研究中，我们还阐明了MCD饮食每DNA每DNA的8hdg次数的增加约为5MEC数量的减少约10 000倍，表明8ohdg形成对DNA甲基化的贡献不会显着。版权所有（c）2015 John Wiley＆Sons，Ltd。

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