DNA methylation is important in regulating gene expression and genomic stability while aberrant DNA methylation is associated with disease. Riboflavin (FAD) is a cofactor for methylenetetrahydrofolate reductase (MTHFR), a critical enzyme in folate recycling, which generates methyl groups for homocysteine remethylation to methionine, the pre-cursor to the universal methyl donor S-adenosylmethionine (SAM). A polymorphism (C677T) in MTHFR results in decreased MTHFR activity and increased homocysteine concentration. Previous studies demonstrated that riboflavin modulates this phenotype in homozygous adults (MTHFR 677 TT genotype), however, DNA methylation was not considered. This study examined DNA methylation, globally and at key MTHFR regulatory sites, in adults stratified by MTHFR genotype and the effect of riboflavin supplementation on DNA methylation in individuals with the 677 TT genotype. Samples were accessed from participants, screened for the MTHFR C677T polymorphism, who participated in observational (n = 80) and targeted riboflavin (1.6 mg/day) RCTs (n = 80). DNA methylation at LINE-1 and key regulatory regions of the MTHFR locus were analysed by pyrosequencing in peripheral blood leukocytes. LINE-1 (+1.6%; p = 0.011) and MTHFR south shelf (+4.7%, p < 0.001) were significantly hypermethylated in individuals with the MTHFR 677 TT compared to CC genotype. Riboflavin supplementation resulted in decreased global methylation, albeit only significant at one CpG. A significant reduction in DNA methylation at the MTHFR north shore (-1.2%, p < 0.001) was also observed in TT adults following intervention with riboflavin. This provides the first RCT evidence that DNA methylation may be modulated by riboflavin in adults with the MTHFR 677 TT genotype.

中文翻译：

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核黄素的补充改变了具有MTHFR 677 TT基因型的成年人的总体和基因特异性DNA甲基化。

DNA甲基化在调节基因表达和基因组稳定性方面很重要，而异常的DNA甲基化则与疾病有关。核黄素（FAD）是亚甲基四氢叶酸还原酶（MTHFR）的辅因子，MTHFR是叶酸循环中的关键酶，它会产生甲基，使高半胱氨酸再甲基化为蛋氨酸，而蛋氨酸是通用甲基供体S-腺苷甲硫氨酸（SAM）的前体。MTHFR中的多态性（C677T）导致MTHFR活性降低和高半胱氨酸浓度增加。先前的研究表明核黄素调节纯合成人（MTHFR 677 TT基因型）的这种表型，但是未考虑DNA甲基化。这项研究检查了全球和主要MTHFR调控位点的DNA甲基化，按MTHFR基因型分层的成年成年人和补充核黄素对677 TT基因型个体的DNA甲基化的影响。从参与者中获取样品，筛选MTHFR C677T多态性，他们参加了观察性（n = 80）和靶向核黄素（1.6 mg /天）RCT（n = 80）。在外周血白细胞中通过焦磷酸测序分析了LINE-1和MTHFR基因座关键调控区的DNA甲基化。与CC基因型相比，具有MTHFR 677 TT的个体中LINE-1（+ 1.6％; p = 0.011）和MTHFR南架（+ 4.7％，p <0.001）显着超甲基化。核黄素的补充导致总体甲基化降低，尽管仅在一个CpG时显着。MTHFR北岸的DNA甲基化显着减少（-1.2％，p <0。核黄素干预后的TT成人中也观察到了001）。这提供了第一个RCT证据，在具有MTHFR 677 TT基因型的成年人中，DNA甲基化可能受核黄素调节。