Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood

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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Integrative modeling of tumor DNA methylation identifies a role for metabolism

10.1101/057638 ◽

2016 ◽

Author(s):

Mahya Mehrmohamadi ◽

Lucas K. Mentch ◽

Andrew G. Clark ◽

Jason W. Locasale

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

Methylation Status ◽

Individual Variability ◽

Early Event ◽

Large Contribution ◽

Cancer Type ◽

Relative Contribution ◽

One Carbon Metabolism ◽

Genomic Regions

AbstractDNA methylation varies across genomic regions, tissues and individuals in a population. Altered DNA methylation is common in cancer and often considered an early event in tumorigenesis. However, the sources of heterogeneity of DNA methylation among tumors remain poorly defined. Here, we capitalize on the availability of multi-platform data on thousands of molecularly-and clinically-annotated human tumors to build integrative models that identify the determinants of DNA methylation. We quantify the relative contribution of clinical and molecular factors in explaining within-cancer (inter-individual) variability in DNA methylation. We show that the levels of a set of metabolic genes involved in the methionine cycle that are constituents of one-carbon metabolism are predictive of several features of DNA methylation status in tumors including the methylation of genes that are known to drive oncogenesis. Finally, we demonstrate that patients whose DNA methylation status can be predicted from the genes in one-carbon metabolism exhibited improved survival over cases where this regulation is disrupted. To our knowledge, this study is the first comprehensive analysis of the determinants of methylation and demonstrates the surprisingly large contribution of metabolism in explaining epigenetic variation among individual tumors of the same cancer type. Together, our results illustrate links between tumor metabolism and epigenetics and outline future clinical implications.

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Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism

Oncogene ◽

10.1038/onc.2017.367 ◽

2017 ◽

Vol 37 (7) ◽

pp. 963-970 ◽

Cited By ~ 44

Author(s):

E Cuyàs ◽

S Fernández-Arroyo ◽

S Verdura ◽

R Á-F García ◽

J Stursa ◽

...

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

Global Dna Methylation ◽

One Carbon Metabolism

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DNA methylation of insulin-like growth factor 2 and H19 cluster in cord blood and prenatal air pollution exposure to fine particulate matter

Environmental Health ◽

10.1186/s12940-020-00677-9 ◽

2020 ◽

Vol 19 (1) ◽

Author(s):

Congrong Wang ◽

Michelle Plusquin ◽

Akram Ghantous ◽

Zdenko Herceg ◽

Rossella Alfano ◽

...

Keyword(s):

Dna Methylation ◽

Particulate Matter ◽

Growth Factor ◽

Cord Blood ◽

Gene Cluster ◽

Methylation Level ◽

Fine Particulate Matter ◽

Methylation Status ◽

Insulin Like Growth Factor ◽

Fine Particulate

Abstract Background The IGF2 (insulin-like growth factor 2) and H19 gene cluster plays an important role during pregnancy as it promotes both foetal and placental growth. We investigated the association between cord blood DNA methylation status of the IGF2/H19 gene cluster and maternal fine particulate matter exposure during fetal life. To the best of our knowledge, this is the first study investigating the association between prenatal PM2.5 exposure and newborn DNA methylation of the IGF2/H19. Methods Cord blood DNA methylation status of IGF2/H19 cluster was measured in 189 mother-newborn pairs from the ENVIRONAGE birth cohort (Flanders, Belgium). We assessed the sex-specific association between residential PM2.5 exposure during pregnancy and the methylation level of CpG loci mapping to the IGF2/H19 cluster, and identified prenatal vulnerability by investigating susceptible time windows of exposure. We also addressed the biological functionality of DNA methylation level in the gene cluster. Results Prenatal PM2.5 exposure was found to have genetic region-specific significant association with IGF2 and H19 during specific gestational weeks. The association was found to be sex-specific in both gene regions. Functionality of the DNA methylation was annotated by the association to fetal growth and cellular pathways. Conclusions The results of our study provided evidence that prenatal PM2.5 exposure is associated with DNA methylation in newborns’ IGF2/H19. The consequences within the context of fetal development of future phenotyping should be addressed.

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Modeling folate, one-carbon metabolism, and DNA methylation

Nutrition Reviews ◽

10.1111/j.1753-4887.2008.00062.x ◽

2008 ◽

Vol 66 ◽

pp. S27-S30 ◽

Cited By ~ 35

Author(s):

Cornelia M Ulrich ◽

Michael C Reed ◽

H Frederik Nijhout

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

One Carbon Metabolism

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Formate concentrations in maternal plasma during pregnancy and in cord blood in a cohort of pregnant Canadian women: relations to genetic polymorphisms and plasma metabolites

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqz152 ◽

2019 ◽

Vol 110 (5) ◽

pp. 1131-1137 ◽

Cited By ~ 5

Author(s):

John T Brosnan ◽

Lesley Plumptre ◽

Margaret E Brosnan ◽

Theerawat Pongnopparat ◽

Shannon P Masih ◽

...

Keyword(s):

Cord Blood ◽

Early Pregnancy ◽

Carbon Metabolism ◽

Critical Role ◽

Plasma Concentrations ◽

Maternal Blood ◽

Plasma Metabolites ◽

Blood Samples ◽

One Carbon Metabolism ◽

Thymidylate Synthesis

ABSTRACT Background One-carbon metabolism, responsible for purine and thymidylate synthesis and transmethylation reactions, plays a critical role in embryonic and fetal development. Formate is a key player in one-carbon metabolism. In contrast to other one-carbon metabolites, it is not linked to tetrahydrofolate, is present in plasma at appreciable concentrations, and may therefore be distributed to different tissues. Objective The study was designed to determine the concentration of formate in cord blood in comparison with maternal blood taken earlier in pregnancy and at delivery and to relate formate concentrations to potential precursors and key fetal genotypes. Methods Formate and amino acids were measured in plasma during early pregnancy (12–16 wk), at delivery (37–42 wk), and in cord blood samples from 215 mothers, of a prospective cohort study. Three fetal genetic variants in one-carbon metabolism were assessed for their association with cord plasma concentrations of formate. Results The formate concentration was ∼60% higher in the cord blood samples than in mothers’ plasma. The maternal formate concentrations did not differ between the early pregnancy samples and those taken at delivery. Plasma concentrations of 4 formate precursors (serine, glycine, tryptophan, and methionine) were increased in cord blood compared with the maternal samples. Cord blood formate was influenced by fetal genotype, being ∼12% higher in infants harboring the MTHFR A1298C (rs1801131) AC or CC genotypes and 10% lower in infants harboring the MTHFD1 G1958A (rs2236225) GA or AA genotypes. Conclusions The increased formate concentrations in cord blood may support the increased activity of one-carbon metabolism in infants. As such, it would support increased rates of purine and thymidylate synthesis and the provision of methionine for methylation reactions.

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Genetic polymorphisms relevant for one-carbon metabolism show no effect on homocysteine plasma levels and DNA methylation in alcoholism

Psychiatric Genetics ◽

10.1097/ypg.0b013e32832cec44 ◽

2009 ◽

Vol 19 (4) ◽

pp. 215-216 ◽

Cited By ~ 1

Author(s):

Bernd Lenz ◽

Carmen Soehngen ◽

Michael Linnebank ◽

Annemarie Heberlein ◽

Helge Frieling ◽

...

Keyword(s):

Dna Methylation ◽

Genetic Polymorphisms ◽

Carbon Metabolism ◽

Plasma Levels ◽

One Carbon Metabolism

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Short-term dietary methionine supplementation affects one-carbon metabolism and DNA methylation in the mouse gut and leads to altered microbiome profiles, barrier function, gene expression and histomorphology

Genes & Nutrition ◽

10.1186/s12263-017-0576-0 ◽

2017 ◽

Vol 12 (1) ◽

Cited By ~ 17

Author(s):

Isabelle R. Miousse ◽

Rupak Pathak ◽

Sarita Garg ◽

Charles M. Skinner ◽

Stepan Melnyk ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Carbon Metabolism ◽

Barrier Function ◽

Short Term ◽

Methionine Supplementation ◽

One Carbon Metabolism

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Study on the Relationship Between Folate, Dna Methylation and Esophagus Cancer

Journal of Clinical and Nursing Research ◽

10.26689/jcnr.v1i3.160 ◽

2017 ◽

Vol 1 (3) ◽

Author(s):

Huang Guiling

Keyword(s):

Dna Methylation ◽

Carbon Metabolism ◽

Early Screening ◽

Methyl Group ◽

Esophagus Cancer ◽

Multiple Factors ◽

Chinese Characteristic ◽

The World ◽

One Carbon Metabolism ◽

The Relationship

Esophagus cancer is a common malignant tumor in China, and itsprevalence rate and fatality rate are the highest in the world whoseoccurrence is related to multiple factors, including family heredity,race, gender, region, diet and so on. Esophagus cancer is the diseasewith the most Chinese characteristic. The pathogenesis of esophagusÂ cancer is very complicated, and the epigenetics in the pathogeneticÂ process has become the current research hotspot, and the reversibleÂ feature provides a new direction for the early screening, preventionÂ and treatment of esophagus cancer. DNA methylation is the mostÂ deep epigenetics in the current study, and the pattern of genomeÂ methylation is often abnormal in the cancerization of esophagusÂ cancer. The folate, as the methyl group donor, and B-vitaminsÂ related to one-carbon metabolism, shall directly influence theÂ condition of DNA methylation, give rise to the change of epigenetics,Â affect the occurrence of esophagus cancer. This paper summarizesÂ the relationship among the occurrence of esophagus cancer andÂ folate, several kinds of B-vitamins related to one-carbon metabolism,Â DNA methylation.

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