A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status

TLDR

DNA methylation, a key epigenetic regulator, depends on the methyl donor S‑adenosyl‑methionine produced via the folate‑dependent enzyme methylenetetrahydrofolate reductase (MTHFR). The study aimed to assess how folate status modulates genomic DNA methylation and whether this effect differs in individuals carrying the common MTHFR C677T mutation. Genomic DNA methylation was quantified by liquid chromatography–mass spectrometry in peripheral blood mononuclear cells from 105 TT and 187 CC subjects. Methylation levels were positively associated with folate, negatively with homocysteine, were lower in TT carriers, and in TT subjects only low folate predicted reduced methylation, indicating that the C677T polymorphism influences DNA methylation through folate status.

Abstract

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-methylTHF), the methyl donor for synthesis of methionine 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 ( T / T ) 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 / T genotypes had a diminished level of DNA methylation compared with those with the C / C wild-type (32.23 vs.62.24 ng 5-methylcytosine/μg 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 T / T 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.