A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status
A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status
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DOI：
10.1073/pnas.062066299
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发表时间：
2002-04-16
影响因子：
11.1
通讯作者：
Selhub, J
中科院分区：
文献类型：
--
作者：
Friso, S;Choi, SW;Selhub, J
DNA甲基化是调节基因表达和基因组完整性的DNA的基本表观遗传特征，由使用通用甲基供体S-腺苷-L-甲硫氨酸的甲基转移酶催化。亚甲基四氢叶酸还原酶（MTHFR）催化5-甲基四氢叶酸（5-methyltetrahydrofolate，5-THF）的合成，5-THF是由同型半胱氨酸合成蛋氨酸的甲基供体，也是S-腺苷-L-蛋氨酸的前体。在本研究中，我们试图确定叶酸状态对基因组DNA甲基化的影响，重点是与MTHFR基因中常见的C677 T突变的相互作用。使用液相色谱/MS法分析核苷酸碱基，以评估105例该突变（TIT）纯合子和187例野生型（C/C）MTHFR基因型纯合子受试者外周血单核细胞DNA中的基因组DNA甲基化。结果表明，基因组DNA甲基化与叶酸水平呈正相关，与血浆同型半胱氨酸（tHcy）水平呈负相关（P < 0.01）。与C/C野生型相比，T/T基因型的DNA甲基化水平降低（32.23对62.24 ng 5-甲基胞嘧啶/mug DNA，P < 0.0001）。然而，当根据叶酸状态进行分析时，只有叶酸水平低的T/T受试者才能解释DNA甲基化的减少（P < 0.0001）。此外，在TIT受试者中，DNA甲基化状态与红细胞叶酸的甲基化比例相关，并且与红细胞叶酸的甲酰化比例呈负相关（P < 0.03），已知甲酰化比例仅在这些个体中存在。这些结果表明MTHFR C677 T多态性通过与叶酸状态的相互作用影响DNA甲基化状态。
DNA methylation, an essential epigenetic feature of DNA that modulates gene expression and genomic integrity, is catalyzed by methyltransferases that use the universal methyl donor S-adenosyl-L-methionine. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate (5-methyl-THF), the methyl donor for synthesis of methlonine from homocysteine and precursor of S-adenosyl-L-methionine. In the present study we sought to determine the effect of folate status on genomic DNA methylation with an emphasis on the interaction with the common C677T mutation in the MTHFR gene. A liquid chromatography/MS method for the analysis of nucleotide bases was used to assess genomic DNA methylation in peripheral blood mononuclear cell DNA from 105 subjects homozygous for this mutation (TIT) and 187 homozygous for the wild-type (C/C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T/Tgenotypes had a diminished level of DNA methylation compared with those with the C/C wild-type (32.23 vs.62.24 ng 5-methylcytosine/mug DNA, P < 0.0001). When analyzed according to folate status, however, only the T/T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in TIT subjects DNA methylation status correlated with the methylated proportion of red blood cell folate and was inversely related to the formylated proportion of red blood cell folates (P < 0.03) that is known to be solely represented in those individuals. These results indicate that the MTHFR C677T polymorphism influences DNA methylation status through an interaction with folate status.