A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with 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-methyl-THF), 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 chromatography͞MS 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 (T͞T) and 187 homozygous for the wild-type (C͞C) MTHFR genotype. The results show that genomic DNA methylation directly correlates with folate status and inversely with plasma homocysteine (tHcy) levels (P < 0.01). T͞T genotypes had a diminished level of DNA methylation compared with those with the C͞C wild-type (32.23 vs.62.24 ng 5-methylcytosine͞g DNA, P < 0.0001). When analyzed according to folate status, however, only the T͞T subjects with low levels of folate accounted for the diminished DNA methylation (P < 0.0001). Moreover, in T͞T 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.

Methionine synthase reductase deficiency results in adverse reproductive outcomes and congenital heart defects in mice

“…Using our Mthfrdeficient mouse model, we demonstrated directly that disruption of the Mthfr gene or low dietary folate adversely affect the developing heart [1]. This finding is likely related to the fact that MTHFR deficiency in humans and mice is associated with low methylTHF, high homocysteine and reduced DNA methylation [21][22][23].…”

Interactions Between MTHFR C677T - A1298C Variants and Folic Acid Deficiency Affect Breast Cancer Risk in a Chinese Population

“…This is counterintuitive because uracil in DNA is positively correlated with MNBN in other studies using this system (Crott et al, 2001). However, MNBN may originate not only from chromosome breakage caused by uracil in DNA, but also from chromosomal loss events that may be caused by hypomethylation of DNA (Friso et al, 2002). One study reported that the 677TT with a mutated 1298 locus genotype increases DNA hypomethylation in lymphocytes in vivo (Campbell et al, 2002), and DNA hypomethylation in lymphocytes in vitro or in vivo increases the loss of chromosomes 1, 9 and 16, which are then included in MNBN (Guttenbach et al, 1994;Xu et al, 1999).…”

DNA digestion to deoxyribonucleoside: A simplified one-step procedure

“…Likewise, in vivo experiments in humans, such as examination of the effect of gene polymorphisms [6] and nutritional status [6,7] on DNA metabolism, have used labeled one-carbon donors to label monocyte DNA. Nucleoside hydrolysates of DNA also have been used in determining the base composition of DNA, including investigation of epigenetic modification such as deoxycytosine methylation [8,9], oxidative damage [10,11], or unique DNA composition [12].…”