Genome-wide hypermethylation coupled with promoter hypomethylation in the chorioamniotic membranes of early onset pre-eclampsia

Mol Hum Reprod. 2014 Sep;20(9):885-904. doi: 10.1093/molehr/gau046. Epub 2014 Jun 18.


Pre-eclampsia is the leading cause of fetal and maternal morbidity and mortality. Early onset pre-eclampsia (EOPE) is a disorder that has severe maternal and fetal outcomes, whilst its etiology is poorly understood. We hypothesize that epigenetics plays an important role to mediate the development of EOPE and conducted a case-control study to compare the genome-wide methylome difference between chorioamniotic membranes from 30 EOPE and 17 full-term pregnancies using the Infinium Human Methylation 450 BeadChip arrays. Bioinformatics analysis tested differential methylation (DM) at CpG site level, gene level, and pathway and network level. A striking genome-wide hypermethylation pattern coupled with hypomethylation in promoters was observed. Out of 385 184 CpG sites, 9995 showed DM (2.6%). Of those DM sites, 91.9% showed hypermethylation (9186 of 9995). Over 900 genes had DM associated with promoters. Promoter-based DM analysis revealed that genes in canonical cancer-related pathways such as Rac, Ras, PI3K/Akt, NFκB and ErBB4 were enriched, and represented biological functional alterations that involve cell cycle, apoptosis, cancer signaling and inflammation. A group of genes previously found to be up-regulated in pre-eclampsia, including GRB2, ATF3, NFKB2, as well as genes in proteasome subunits (PSMA1, PMSE1, PSMD1 and PMSD8), harbored hypomethylated promoters. Contrarily, a cluster of microRNAs, including mir-519a1, mir-301a, mir-487a, mir-185, mir-329, mir-194, mir-376a1, mir-486 and mir-744 were all hypermethylated in their promoters in the EOPE samples. These findings collectively reveal new avenues of research regarding the vast epigenetic modifications in EOPE.

Keywords: DNA methylation; bioinformatics; chorioamniotic membranes; epigenetics; pre-eclampsia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amnion / metabolism*
  • Case-Control Studies
  • Chorion / metabolism*
  • Computational Biology
  • DNA / metabolism
  • DNA Methylation*
  • Down-Regulation
  • Epigenesis, Genetic*
  • Female
  • Genome-Wide Association Study
  • Humans
  • MicroRNAs / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Pre-Eclampsia / metabolism*
  • Pregnancy
  • Promoter Regions, Genetic*
  • Retrospective Studies
  • Up-Regulation
  • Young Adult


  • MicroRNAs
  • DNA