Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism

ABSTRACT Background Nonruminant male and female offspring respond differently to gestational nutrition, with placenta contributing to the underlying mechanisms. However, similar data are lacking in large ruminants. Objectives The aim of this study was to investigate the impact of methionine supply during late-gestation on metabolism and DNA methylation in placenta from cows carrying male or female calves. Methods During the last 28 d of pregnancy, cows were individually fed a control diet (CON) or the control diet plus rumen-protected d,l-methionine (MET; 0.9 g/kg dry matter intake). Placentomes collected at term were classified according to cow dietary treatment and offspring sex as follows: Male CON (n = 7), Male MET (n = 7), Female CON (n = 8), and Female MET (n = 8). Calf growth was measured until 9 wk of age. Targeted metabolomics, RT-PCR, global DNA methylation, and activity of selected enzymes in one-carbon metabolism and transsulfuration pathways were performed. Statistics were conducted via ANOVA using MIXED models. Results At birth, Male MET calves were heavier than Male CON calves (7.6%, P = 0.02), but body mass was similar at 9 wk of age. In contrast, compared with Female CON, Female MET calves had greater body mass at 9 wk of age (6.3%, P = 0.03). Compared with Male CON, placenta from Male MET calves had greater concentrations of tricarboxylic acid (TCA) cycle and transsulfuration intermediates (23–100%, P < 0.05), along with greater 5-methyltetrahydrofolatehomocysteine methyltransferase activity (67%, P = 0.03). Compared with Female CON, placenta from Female MET calves had greater concentrations of one-carbon metabolism intermediates (13–52%, P < 0.05). DNA methyltransferase 3A (DNMT3A) was upregulated (43%, P < 0.01) in placenta from Female MET compared with Female CON calves. Global DNA methylation was lower in placenta from Female MET compared with Female CON calves (45%, P = 0.06). Conclusions Methionine supply affects placental metabolism, DNA methylation, and body mass of the calf in a sex-specific manner, underscoring its importance as dietary methyl-donor for pregnant cows.

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DNA methylation and one-carbon metabolism related nutrients and polymorphisms: analysis after mandatory flour fortification with folic acid

British Journal Of Nutrition ◽

10.1017/s0007114519002526 ◽

2019 ◽

Vol 123 (1) ◽

pp. 23-29 ◽

Cited By ~ 2

Author(s):

Josiane Steluti ◽

Cecília Zanin Palchetti ◽

Andreia Machado Miranda ◽

Regina Mara Fisberg ◽

Dirce Maria Marchioni

Keyword(s):

Dna Methylation ◽

Folic Acid ◽

Carbon Metabolism ◽

The Elderly ◽

Cross Sectional Study ◽

Global Dna Methylation ◽

Cross Sectional ◽

Absolute Change ◽

Global Status ◽

One Carbon Metabolism

AbstractThere is a growing research interest in determining whether changes in the global status of DNA methylation are related to the environment, in particular, to one-carbon metabolism. So, our aim was to investigate the effect of dietary methyl-group donor intake (methionine, folate, choline, betaine, vitamins B2, B6 and B12), biomarkers (total folate, unmetabolised folic acid (FA), 5-methyltetrahydrofolate, homocysteine, vitamins B6 and B12 concentrations) and genetic variants (polymorphisms involved in one-carbon metabolism) on global DNA methylation in a population exposed to mandatory flour fortification with FA. A cross-sectional study of health and living conditions was conducted among a representative sample of residents in São Paulo, Brazil. The mean of global DNA methylation was lower in young people than in adults and the elderly (P = 0·049). No differences between genotypes of polymorphism and global DNA methylation mean were identified. We observed that the increase in betaine intake led to an absolute change in percentage of DNA methylation (β = 0·0005, P = 0·024) using multiple regression. Betaine intake alone was associated with an absolute change in percentage of global DNA methylation. The study did not find an association between global DNA methylation and folate status even in a population exposed to mandatory flour fortification with FA.

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Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms19103106 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3106 ◽

Cited By ~ 19

Author(s):

Kuniyasu Soda

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

Methylation Status ◽

Significant Risk ◽

Significant Risk Factor ◽

Dna Methyltransferases ◽

Polyamine Metabolism ◽

Methyl Group ◽

Wide Range ◽

One Carbon Metabolism

Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.

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