Effect of imbalance in folate and vitamin B12 in maternal/parental diet on global methylation and regulatory miRNAs

Abstract

DNA methylation, a central component of the epigenetic network is altered in response to nutritional influences. In one-carbon cycle, folate acts as a one-carbon carrier and vitamin B12 acts as co-factor for the enzyme methionine synthase. Both folate and vitamin B12 are the important regulators of DNA methylation which play an important role in development in early life. Previous studies carried out in this regard have shown the individual effects of these vitamins but recently the focus has been to study the combined effects of both the vitamins during pregnancy. Therefore, this study was planned to elucidate the effect of the altered dietary ratio of folate and B12 on the expression of transporters, related miRNAs and DNA methylation in C57BL/6 mice. Female mice were fed diets with 9 combinations of folate and B12 for 4 weeks. They were mated and off-springs born (F1) were continued on the same diet for 6 weeks post-weaning. Maternal and fetal (F2) tissues were collected at day 20 of gestation. Deficient state of folate led to an increase in the expression of folate transporters in both F1 and F2 generations, however, B12 deficiency (BDFN) also led to an increase in the expression in both the generations. B12 transporters/proteins were found to be increased with B12 deficiency in F1 and F2 generations except for TC-II in the kidney which was found to be decreased in the F1 generation. miR-483 was found to be increased with all conditions of folate and B12 in both F1 and F2 generations, however, deficient conditions of B12 led to an increase in the expression of miR-221 in both F1 and F2 generations. The level of miR-133 was found to be increased in BDFN group in F1 generation however; in F2 generation the change in expression was tissue and sex-specific. Global DNA methylation was decreased with deficiency of both folate and B12 in maternal tissues (F1) but increased with folate deficiency in placenta (F1) and under all conditions in fetal tissues (F2). DNA methyltransferases were overall found to be increased with deficiency of folate and B12 in both F1 and F2 generations. Results suggest that the dietary ratio of folate and B12 resulted in altered expression of transporters, miRNAs, and genomic DNA methylation in association with DNMTs.

Vitamin B12 Induces Hepatic Fatty Infiltration through Altered Fatty Acid Metabolism

“…These data therefore highlight the potential importance of de novo lipogenesis and these individual fatty acids in the low B12 status which might predispose to development of T2D and other related co-morbidities. Whether B12 plays an epigenetic role in the synthesis of 16:0 and 18:0 fatty acids, similar to our previous observations on adipocytes [14,15] and animal studies [13,48], requires future studies.…”

Epigenetics of Hepatic Insulin Resistance

“…Maternal folate supplements have been associated with decreased levels of global DNA methylation in offspring liver (174). This negative relationship is surprising, although similar results have been reported elsewhere (175) and has been suggested to result from the altered methylation of DNMTs (174,175). It is also worth noting that folate has other functions aside from acting as a methyl donor, for example regulating the lysine demethylase LDS1, such that folate deficiency leads to increased levels of active histone marks H3K4me1/2 in the liver of rodents (176).…”

Differential ESR1 Promoter Methylation in the Peripheral Blood—Findings from the Women 40+ Healthy Aging Study

“…At last, in this study, we did not assess data linked to women's nutritional status, such as B12 and red cell folate, which have been shown to regulate DNA methylation [71].…”