Differential Methylation of Genes Associated with Cell Adhesion in Preeclamptic Placentas

Abstract

Preeclampsia (PE), a hypertensive disorder of pregnancy, is hypothesized to be associated with, if not mechanistically related to abnormal placental function. However, the exact mechanisms regulating the pathogenesis of PE remain unclear. While many studies have investigated changes in gene expression in the PE placenta, the role of epigenetics in PE associated placental dysfunction remains unclear. Using the genome-wide Illumina Infinium Methylation 450 BeadChip array, we analyzed gene-specific alterations in DNA methylation in placental biopsies collected from normal pregnant women delivering at term (n = 14), with term PE (≥37 weeks; n = 19) or with preterm PE (<37 weeks, n = 12). Of the 485,582 gene loci on the array, compared to controls, 229 loci were differentially methylated in PE placentas and 3411 loci were differentially methylated in preterm PE (step up p-value <0.05 and >5% methylation difference). Functional annotation of the differentially methylated genes in preterm PE placentas revealed a 32 gene cluster in the cadherin and cell adhesion functional groups (Benjamini p<0.00001). Hypermethylation of CDH11 (p = 0.0143), COL5A1 (p = 0.0127) and TNF (p = 0.0098) and hypomethylation of NCAM1 (p = 0.0158) was associated with altered mRNA expression in preterm PE placentas. Demethylation of first trimester extravillous trophoblast cells resulted in altered CDH11 (p = 0.0087), COL5A1 (p = 0.0043), NCAM1 (p = 0.0260) and TNF (p = 0.0022) mRNA expression. These studies demonstrate aberrant methylation, correlating with disease severity, in PE placentas. Furthermore, we provide evidence that disruption of gene-specific methylation in preterm PE placentas and first trimester trophoblasts is significantly associated with altered gene expression demonstrating that epigenetic modifications early in pregnancy can have effects on trophoblast function contributing to PE.

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.…”

High‐resolution analysis of the human placental DNA methylome in early gestation

“…DNA methylation is intimately linked to chromatin structure, genome function, and placental phenotype. Multiple reports exist of abnormal fetal epigenetic programing in mothers with gestational diabetes, nutritional deficiency, tobacco exposure, synthetic estrogens, and preeclampsia . To improve our understanding of how the maternal environment influences fetal programming, it is important to further our understanding of pregnancy‐specific epigenetic profiles both in the placental and maternal compartments.…”

Paternal obesity in a rodent model affects placental gene expression in a sex-specific manner

“…Paternally expressed genes tend to enhance fetal and placental growth, while maternally expressed genes have the converse effect (Lim & Ferguson-Smith 2010), and as such, hypermethylation of paternally expressed genes may result in FGR. Placental hypermethylation has also been linked to other complications of pregnancy including preeclampsia and placental mesenchymal dysplasia, both of which are associated with increased rates of FGR and fetal death (Anton et al 2014, Chen et al 2014. Interestingly, a rodent model of gestational diabetes has shown overlap between differentially methylated genes in the placenta and fetal tissues, which affect metabolic pathways (Petropoulos et al 2015).…”