The role of aberrant methylation of trophoblastic stem cell origin in the pathogenesis and diagnosis of placental disorders.

Abstract

The objective of the study is to investigate the role of methylation levels at promoter regions of placental vascularization genes (VEGF, EGFR, and c-jun) in pathogenesis and diagnosis of placental disorders. We analyzed DNA and histone methylation at promoters of VEGF, EGFR, and c-jun via methylation-sensitive high-resolution melting and chromatin immunoprecipitation assay in pregnant women with normal pregnancy in first, second, and third trimesters (n = 30 in each group) and pregnant women with pregnancy complicated with preeclampsia (n = 30) and hydatidiform mole (n = 15). The higher expression of VEGF, EGFR, and c-jun in early pregnancy was observed to be independent of DNA methylation, while it was associated with H3 K9/K27 trimethylations. Also, abnormally higher expression of c-jun in GTDs was associated with lower H3K9me3 level at its promoter. Under preeclampsia conditions, we observed dysregulation of both DNA methylation and H3 trimethylation and subsequent low expression of VEGF, EGFR, and c-jun. Importantly, our promoter methylation data indicated that VEGF may act as novel fetal DNA diagnostic marker for preeclampsia and molar pregnancies in maternal plasma. These findings emphasize the importance of dysregulated epigenetic phenomenon behind the pathologies of placental disorders and use of promoter region DNA methylation as an epigenetic marker for these pathological pregnancies. © 2016 John Wiley & Sons, Ltd.