Dataset Information

A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.

ABSTRACT:

Background

Maternal blood folate concentrations during pregnancy have been previously linked with DNA methylation patterns, but this has been done predominantly through observational studies. We showed recently in an epigenetic analysis of the first randomized controlled trial (RCT) of folic acid supplementation specifically in the second and third trimesters (the EpiFASSTT trial) that methylation at some imprinted genes was altered in cord blood samples in response to treatment. Here, we report on epigenome-wide screening using the Illumina EPIC array (~?850,000 sites) in these same samples (n?=?86).

Results

The top-ranked differentially methylated promoter region (DMR) showed a gain in methylation with folic acid (FA) and was located upstream of the imprint regulator ZFP57. Differences in methylation in cord blood between placebo and folic acid treatment groups at this DMR were verified using pyrosequencing. The DMR also gains methylation in maternal blood in response to FA supplementation. We also found evidence of differential methylation at this region in an independent RCT cohort, the AFAST trial. By altering methylation at this region in two model systems in vitro, we further demonstrated that it was associated with ZFP57 transcription levels.

Conclusions

These results strengthen the link between folic acid supplementation during later pregnancy and epigenetic changes and identify a novel mechanism for regulation of ZFP57. This trial was registered 15 May 2013 at www.isrctn.com as ISRCTN19917787.

SUBMITTER: Irwin RE

PROVIDER: S-EPMC6380035 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.

Irwin Rachelle E RE Thursby Sara-Jayne SJ Ondičová Miroslava M Pentieva Kristina K McNulty Helene H Richmond Rebecca C RC Caffrey Aoife A Lees-Murdock Diane J DJ McLaughlin Marian M Cassidy Tony T Suderman Matthew M Relton Caroline L CL Walsh Colum P CP

Clinical epigenetics 20190218 1

<h4>Background</h4>Maternal blood folate concentrations during pregnancy have been previously linked with DNA methylation patterns, but this has been done predominantly through observational studies. We showed recently in an epigenetic analysis of the first randomized controlled trial (RCT) of folic acid supplementation specifically in the second and third trimesters (the EpiFASSTT trial) that methylation at some imprinted genes was altered in cord blood samples in response to treatment. Here, w ...[more]

PMID: 30777123

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Project description:BACKGROUND:It has been proposed that maternal folic-acid supplement use may alter the DNA-methylation patterns of the offspring during the in-utero period, which could influence development and later-life health outcomes. Evidence from human studies suggests a role for prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood. METHODS:To better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen Folic Acid Supplementation Trial (AFAST-a trial of two different doses: 0.2 and 5?mg, folic acid vs placebo). Offspring of the AFAST participants were recruited at a mean age of 47?years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single-site and differentially methylated region analyses were performed. RESULTS:We found an association at cg09112514 (p?=?4.03×10-9), a CpG located in the 5' untranslated region of PDGFRA, in the main analysis comparing the intervention arms [low- (0.2?mg) and high-dose (5?mg) folic acid combined (N?=?43)] vs placebo (N?=?43). Furthermore, a dose-response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome that were differentially methylated in response to the intervention (Sidak p-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2-1. Whereas cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8. CONCLUSIONS:The results of this study suggest that maternal folic-acid supplement use is associated with changes in the DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.

Dataset Information

A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.

Background

Results

Conclusions

Publications

A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.

Similar Datasets

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