title: 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.affiliation: Molecular Bioscience and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, HI 96822, USA Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Travers
authors.initials: T
authors.lastname: Ching
authors.affiliation: Molecular Bioscience and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, HI 96822, USA Genomics Shared Resources Core, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Min-Ae
authors.initials: MA
authors.lastname: Song
authors.affiliation: Genomics Shared Resources Core, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Maarit
authors.initials: M
authors.lastname: Tiirikainen
authors.affiliation: Genomics Shared Resources Core, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Janos
authors.initials: J
authors.lastname: Molnar
authors.affiliation: Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA mberry@hawaii.edu towner@hawaii.edu lgarmire@cc.hawaii.edu.
authors.forename: Marla
authors.initials: M
authors.lastname: Berry
authors.affiliation: Department of Obstetrics, Gynecology and Women's Health, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96826, USA mberry@hawaii.edu towner@hawaii.edu lgarmire@cc.hawaii.edu.
authors.forename: Dena
authors.initials: D
authors.lastname: Towner
authors.affiliation: Molecular Bioscience and Bioengineering Graduate Program, University of Hawaii at Manoa, Honolulu, HI 96822, USA Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA mberry@hawaii.edu towner@hawaii.edu lgarmire@cc.hawaii.edu.
authors.forename: Lana X
authors.initials: LX
authors.lastname: Garmire
mesh_terms: D000328:Adult; D000650:Amnion / Q000378:metabolism*; D016022:Case-Control Studies; D002823:Chorion / Q000378:metabolism*; D019295:Computational Biology; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D004247:DNA
keywords: DNA methylation; bioinformatics; chorioamniotic membranes; epigenetics; pre-eclampsia