title: Early onset pre-eclampsia is associated with altered DNA methylation of cortisol-signalling and steroidogenic genes in the placenta.
abstract: Placental cortisol is inactivated in normotensive pregnancies, but is frequently present in pre-eclampsia associated placentae. Since glucocorticoids are strongly associated with the programming of long-term health, we assessed DNA methylation of genes involved in cortisol signalling and bioavailability, and hormonal signalling in the placenta of normotensive and hypertensive pregnancies. Candidate genes/CpG sites were selected through analysis of Illumina Infinium HumanMethylation450 BeadChip array data on control (n = 19) and early onset pre-eclampsia (EOPET; n = 19) placental samples. DNA methylation was further quantified by bisulfite pyrosequencing in a larger cohort of control (n = 111) cases, in addition to EOPET (n = 19), late onset pre-eclampsia (LOPET; n = 18) and normotensive intrauterine growth restriction (nIUGR; n = 13) cases. DNA methylation (percentage points) was increased at CpG sites within genes encoding the glucocorticoid receptor (NR3C1 exon 1D promoter; +8.46%; P<0.01) and corticotropin releasing hormone (CRH) binding protein (CRHBP intron 3; +9.14%; P<0.05), and decreased within CRH (5' UTR; -4.30%; P = 0.11) in EOPET-associated placentae, but not in LOPET nor nIUGR cases, compared to controls. Differential DNA methylation was not observed among groups at the 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) gene promoter. Significant hypomethylation was observed in pre-eclampsia but not nIUGR placentae for steroidogenic genes, including CYP11A1 (exon1; EOPET; -9.66%; P<0.00001, and LOPET; -5.77%; P<0.001), 3β-hydroxy-delta-5-steroid dehydrogenase type 1 (HSD3B1 exon 2; EOPET; -12.49%; P<0.00001, and LOPET; -6.88%; P<0.001), TEA domain family member 3 (TEAD3 intron 1; EOPET; -12.56%; P<0.00001) and CYP19 (placental-specific exon 1.1 promoter; EOPET; -10.62%, P<0.0001). These data represent dysregulation of the placental epigenome in pre-eclampsia related to genes involved in maintaining the hormonal environment during pregnancy and highlights particular susceptibility in the early onset syndrome.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hogg
authors.forename: John D
authors.initials: JD
authors.lastname: Blair
authors.forename: Deborah E
authors.initials: DE
authors.lastname: McFadden
authors.forename: Peter
authors.initials: P
authors.lastname: von Dadelszen
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
mesh_terms: D000328:Adult; D019175:DNA Methylation; D005091:Exons / Q000235:genetics; D005260:Female; D005865:Gestational Age; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis / Q000378:metabolism*; D007745:Labor Onset / Q000235:genetics / Q000378:metabolism; D008297:Male; D010920:Placenta / Q000378:metabolism* / Q000473:pathology*; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013312:Stress, Physiological / Q000235:genetics; D013997:Time Factors
chemical_list: D005938:Glucocorticoids; C497713:NR3C1 protein, human; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D006854:Hydrocortisone