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

Abstract

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.

• Authors: Travers Ching, Min-Ae Song, Maarit Tiirikainen, Janos Molnar, Marla Berry, Dena Towner, Lana X Garmire
• Journal: Molecular human reproduction (Mol Hum Reprod) Vol. 20 Issue 9 Pg. 885-904 (Sep 2014) ISSN: 1460-2407 [Electronic] England
• PMID: 24944161 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• MicroRNAs
• DNA

Topics

• 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