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

Rachelle Irwin, Sara-Jayne Thursby, Miroslava Ondičová, Kristina Pentieva, Helen McNulty, Rebecca Richmond, Aoife Caffrey, Diane Lees-Murdock, Marian McLaughlin, Tony Cassidy, Matthew Suderman, Caroline Relton, Colum Walsh

Research output: Contribution to journalArticle (Academic Journal)peer-review

12 Citations (Scopus)
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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.
Original languageEnglish
Article number31
Number of pages16
JournalClinical Epigenetics
Volume11
Issue number1
Early online date21 Feb 2019
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • Folic acid
  • DNA methylation
  • cord blood
  • offspring
  • imprinting
  • ZFP57

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