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.

Early- and late-onset preeclampsia and the DNA methylation of circadian clock and clock-controlled genes in placental and newborn tissues

“…finding that in EOPE most DMCs were hypomethylated in placental tissue and hypermethylated in UCL and substantiated by other epigenetic studies of candidate genes in PE (Anton et al, 2014;Blair et al, 2013;Hogg et al, 2013;Sundrani et al, 2013;Yuen et al, 2010). The opposite direction of methylation in placental tissue and UCL might be explained by differences in tissue sensitivity and the level of exposure.…”

Elevated Adenosine Induces Placental DNA Hypomethylation Independent of A2B Receptor Signaling in Preeclampsia

“…[15][16][17] However, the factors responsible for widespread placental DNA hypomethylation in preeclampsia have not been identified.…”

The Human Placental Methylome

“…These include, for example, up-regulation of System A transporters, which are responsible for transporting amino acids to the fetus (Coan et al 2010;Burton and Fowden 2012), iron transport proteins (Bradley et al 2004), which absorb iron from maternal blood, and placental corticotropin releasing hormone (CRH), which may stimulate maternal glucose production needed to support the growing brain (Gangestad et al 2012). CRH gene promoter DNA methylation has been correlated with its expression in the placenta (Jiang et al 2012); increased gestational age was associated with decreased DNA methylation at CpG sites associated with the CRH gene as well as other cortisol signaling and steroidogenic genes in the placenta (Hogg et al 2013a). Increased DNA methylation at the promoter region of SLC2A3, the gene encoding the glucose transporter GLUT3, was associated with decreased GLUT3 expression through gestation ).…”