Table 1.

PE-related changes in DNA methylation.

Target Genes	DNA Methylation Changes	Functional Roles	Pregnancy Effects	References
11β-HSD2	Hypo-methylation	Plays a critical role in hypertension, plays an important role in the regulation of blood pressure by preventing the activation of the mineralocorticoid receptor in tissues such as the placenta.	Pregnancy and maternal distress affect placental HSD11B4; during the third trimester, the impact of depression and anxiety symptoms is greater than in the first trimester.	[58,59]
RUNX3	Hypo-methylation	Regularly deleted or transcriptionally silenced in cancer; was selected for analysis because tumor progression and gestation reveal several general features, for example, immune tolerance and invasion.	Significant increases in RUNX3 mRNA expression levels were reported among female smokers relative to nonsmoking women. RUNX3 has been established to be fundamental for promoting Th1 phenotypes through IL-4 repression.	[58]
LINE-1-elements	Hypo-methylation	Prevents activation of the placental mineralocorticoid receptor. Associated with cardiovascular disease and with risk factors for both cardiovascular disease and preterm birth.	Significant decreases in LINE-1 element methylation levels were observed in placentas during the third trimester relative to the first trimester. Hypomethylation of LINE-1 elements has been associated to pathological processes, as well as tumorigenesis, abnormal placental function, birth defects, aging, and chronic diseases.	[58]
IGF-1	Hyper-methylation	Involved in placental formation and fetal growth; associated with increased DNMT1 expression.	Maternal IGF-1 levels are negatively correlated with pregnancies complicated by pre-eclampsia. Higher maternal IGF-1 concentrations have been reported.	[60]
VHL	Hyper-methylation	Codes for a tumor suppressor protein that is critical for normal placental development.	Gestation in patients with VHL disease stimulates cerebellar hemangioblastoma progression and affects the high VHL disorder-related pregnancy complication rate.	[61]
RASSF1A	Hyper-methylation	Activated by promoter hyper-methylation in many tumor types.	Increased levels in the placenta in complicated pregnancies.	[62]

Abbreviations: 11β-HSD: L11β-Hydroxysteroid dehydrogenase type2, RUNX3: RUNX Family Transcription Factor 3, IGF-1: Insulin-like growth factor 1, VHL: von Hippel-Lindau tumor suppressor and RASSF1A: Ras association domain family member 1.