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

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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.
LanguageEnglish
Article number31
Number of pages16
JournalClinical Epigenetics
Volume11
Issue number1
DOIs
Publication statusPublished - 18 Feb 2019

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Folic Acid
Methylation
Randomized Controlled Trials
Pregnancy
Genetic Promoter Regions
Fetal Blood
Epigenomics
Third Pregnancy Trimester
Second Pregnancy Trimester
DNA Methylation
Observational Studies
Placebos
Mothers
Therapeutics
Genes

Keywords

  • Cord blood
  • DNA methylation
  • Folic acid
  • Imprinting
  • Offspring
  • ZFP57

Cite this

@article{7711d4d7c3df4fdda6206cc4cff25327,
title = "A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.",
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.",
keywords = "Cord blood, DNA methylation, Folic acid, Imprinting, Offspring, ZFP57",
author = "Irwin, {Rachelle E} and Sara-Jayne Thursby and Miroslava Ondicova and K. Pentieva and H McNulty and Rebecca Richmond and Aoife Caffrey and {Lees Murdock}, Diane and Marian McLaughlin and T CASSIDY and Matthew Sudderman and Caroline Relton and CP Walsh",
year = "2019",
month = "2",
day = "18",
doi = "10.1186/s13148-019-0618-0",
language = "English",
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T1 - A randomized controlled trial of folic acid intervention in pregnancy highlights a putative methylation-regulated control element at ZFP57.

AU - Irwin, Rachelle E

AU - Thursby, Sara-Jayne

AU - Ondicova, Miroslava

AU - Pentieva, K.

AU - McNulty, H

AU - Richmond, Rebecca

AU - Caffrey, Aoife

AU - Lees Murdock, Diane

AU - McLaughlin, Marian

AU - CASSIDY, T

AU - Sudderman, Matthew

AU - Relton, Caroline

AU - Walsh, CP

PY - 2019/2/18

Y1 - 2019/2/18

N2 - 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.

AB - 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.

KW - Cord blood

KW - DNA methylation

KW - Folic acid

KW - Imprinting

KW - Offspring

KW - ZFP57

U2 - 10.1186/s13148-019-0618-0

DO - 10.1186/s13148-019-0618-0

M3 - Article

VL - 11

IS - 1

M1 - 31

ER -