Genetic and Non-Genetic Influences during Pregnancy on Infant Global and Site Specific DNA Methylation: Role for Folate Gene Variants and Vitamin B12

McKay, Jill A.; Groom, Alix; Potter, Catherine; Coneyworth, Lisa J.; Ford, Dianne; Mathers, John C.; Relton, Caroline L

doi:10.1371/journal.pone.0033290

Cited by 139 publications

(119 citation statements)

References 66 publications

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“…The following possible confounders were based on expertise and literature review (Steegers-Theunissen et al 2009, Obermann-Borst et al 2011, McKay et al 2012.…”

Section: Covariatesmentioning

confidence: 99%

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

Mil¹,

Bouwland-Both²,

Stolk³

et al. 2014

Reproduction

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Correspondence should be addressed to R P M Steegers-Theunissen; Email: r.steegers@erasmusmc.nl † R P M Steegers-Theunissen is now at Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Centre Rotterdam, The Netherlands AbstractMaternal one-carbon (1-C) metabolism provides methylgroups for fetal development and programing by DNA methylation as one of the underlying epigenetic mechanisms. We aimed to investigate maternal 1-C biomarkers, folic acid supplement use, and MTHFR C677T genotype as determinants of 1-C metabolism in early pregnancy in association with newborn DNA methylation levels of fetal growth and neurodevelopment candidate genes. The participants were 463 mother-child pairs of Dutch national origin from a large populationbased birth cohort in Rotterdam, The Netherlands. In early pregnancy (median 13.0 weeks, 90% range 10.4-17.1), we assessed the maternal folate and homocysteine blood concentrations, folic acid supplement use, and the MTHFR C677T genotype in mothers and newborns. In newborns, DNA methylation was measured in umbilical cord blood white blood cells at 11 regions of the seven genes: NR3C1, DRD4, 5-HTT, IGF2DMR, H19, KCNQ1OT1, and MTHFR. The associations between the 1-C determinants and DNA methylation were examined using linear mixed models. An association was observed between maternal folate deficiency and lower newborn DNA methylation, which attenuated after adjustment for potential confounders. The maternal MTHFR TT genotype was significantly associated with lower DNA methylation. However, maternal homocysteine and folate concentrations, folic acid supplement use, and the MTHFR genotype in the newborn were not associated with newborn DNA methylation. The maternal MTHFR C677T genotype, as a determinant of folate status and 1-C metabolism, is associated with variations in the epigenome of a selection of genes in newborns. Research on the implications of these variations in methylation on gene expression and health is recommended.

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“…The following possible confounders were based on expertise and literature review (Steegers-Theunissen et al 2009, Obermann-Borst et al 2011, McKay et al 2012.…”

Section: Covariatesmentioning

confidence: 99%

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

Mil¹,

Bouwland-Both²,

Stolk³

et al. 2014

Reproduction

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“…Examples of such modifications are known from some types of cancer, where hypomethylation of oncogenes and hypermethylation of tumour suppressor genes are supposed components in cancer development [2,4,5]. Epigenetic profiles are influenced by genetics [6][7][8], but ageing and environmental factors including diet, chemicals and smoking may take centre-stage in the control of DNA methylation [9][10][11][12]. Studies have indicated that DNA methylation may play a role in metabolic diseases such as diabetes.…”

Section: Introductionmentioning

confidence: 99%

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

et al. 2012

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Aims/hypothesis Energy-dense diets that are high in fat are associated with a risk of metabolic diseases. The underlying molecular mechanisms could involve epigenetics, as recent data show altered DNA methylation of putative type 2 diabetes candidate genes in response to high-fat diets. We examined the effect of a short-term high-fat overfeeding (HFO) diet on genome-wide DNA methylation patterns in human skeletal muscle. Methods Skeletal muscle biopsies were obtained from 21 healthy young men after ingestion of a short-term HFO diet and a control diet, in a randomised crossover setting. DNA methylation was measured in 27,578 CpG sites/14,475 genes using Illumina's Infinium Bead Array. Candidate gene expression was determined by quantitative real-time PCR. Results HFO introduced widespread DNA methylation changes affecting 6,508 genes (45%), with a maximum methylation change of 13.0 percentage points. The HFO-induced methylation changes were only partly and non-significantly reversed after 6-8 weeks. Alterations in DNA methylation levels primarily affected genes involved in inflammation, the reproductive system and cancer. Few gene expression changes were observed and these had poor correlation to DNA methylation. Conclusions/interpretation The genome-wide DNA methylation changes induced by the short-term HFO diet could have implications for our understanding of transient epigenetic regulation in humans and its contribution to the development of metabolic diseases. The slow reversibility suggests a methylation build-up with HFO, which over time may influence gene expression levels.

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“…Epigenetic differences may not only be secondary to exposure (ART or other in utero exposure) but may also be dependent on the maternal genotype. A recent study found that polymorphisms in genes involved in folate absorption and metabolism may affect DNA methylation patterns (McKay et al 2012). Abnormal methylation of paternal DNA is also important to study because DNA methylation may be altered in the sperm of men with infertility.…”

Section: Resultsmentioning

confidence: 99%

A Molecular Perspective on Procedures and Outcomes with Assisted Reproductive Technologies

Mainigi

Sapienza

Butts

et al. 2016

Cold Spring Harb Perspect Med

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The emerging association of assisted reproductive technologies with adverse perinatal outcomes has prompted the in-depth examination of clinical and laboratory protocols and procedures and their possible effects on epigenetic regulatory mechanism(s). The application of various approaches to study epigenetic regulation to problems in reproductive medicine has the potential to identify relative risk indicators for particular conditions, diagnostic biomarkers of disease state, and prognostic indicators of outcome. Moreover, when applied genome-wide, these techniques are likely to find novel pathways of disease pathogenesis and identify new targets for intervention. The analysis of DNA methylation, histone modifications, transcription factors, enhancer binding and other chromatin proteins, DNasehypersensitivity and, micro-and other noncoding RNAs all provide overlapping and often complementary snapshots of chromatin structure and resultant "gene activity." In terms of clinical application, the predictive power and utility of epigenetic information will depend on the power of individual techniques to discriminate normal levels of interindividual variation from variation linked to a disease state. At present, quantitative analysis of DNA methylation at multiple loci seems likely to hold the greatest promise for achieving the level of precision, reproducibility, and throughput demanded in a clinical setting.

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Genetic and Non-Genetic Influences during Pregnancy on Infant Global and Site Specific DNA Methylation: Role for Folate Gene Variants and Vitamin B12

Cited by 139 publications

References 66 publications

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

A Molecular Perspective on Procedures and Outcomes with Assisted Reproductive Technologies

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