Abstract
BackgroundMaternal 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).ResultsThe 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.ConclusionsThese 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.
Highlights
Maternal blood folate concentrations during pregnancy have been previously linked with DNA methylation patterns, but this has been done predominantly through observational studies
We have previously reported data from a randomized controlled trial of Folic Acid Supplementation in the Second and Third Trimester (The FASSTT Trial; ISRCTN19917787) where we found supplementation led to significant protection against folate depletion in mothers and offspring [42] and more recently that this led to differences in DNA methylation at some imprinted loci by using a candidate gene approach [43]
At baseline (gestational week 14 (GW14)), there were no detectable differences between the treatment and placebo groups in maternal characteristics, dietary folate intakes, serum or red blood cell (RBC) folate concentrations, or in methylenetetrahydrofolate reductase (MTHFR) status, as expected following randomization
Summary
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 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. Observational studies have indicated that FA supplement use by mothers during pregnancy is associated with better cognitive health and brain development in the child [14, 18, 19], possibly related to the fact that there is a brain growth spurt at the end of the second trimester [20, 21]. There may be potential adverse effects from excess folate in later pregnancy, an aspect which would benefit from further exploration [12]
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