Hypoxia Inducible Factors ( HIF1α and HIF3α ) are differentially methylated in preeclampsia placentae and are associated with birth outcomes

Preeclampsia is a placental vascular pathology and hypoxia is known to influence placental angiogenesis. Hypoxia Inducible Factors ( HIF1α and HIF3α ) mediate the response to cellular oxygen concentration and bind to hypoxia response element of target genes. However the mechanism regulating above activity is not well-understood. We investigated if placental DNA methylation (DNAm) and expression of HIF1α and 3α genes are altered and associated with pre-eclampsia, placental weight and birth outcomes. Using a cohort comprising women with preeclampsia [ N = 100, delivering at term ( N = 43) and preterm ( N = 57)] and normotensive controls ( N = 100), we analysed DNAm in HIF1α and 3α, and their mRNA expression in placentae, employing pyrosequencing and quantitative real-time PCR, respectively. We observed significant hypermethylation at cg22891070 of HIF3α in preeclampsia placentae compared to controls ( β = 1.5%, p = 0.04). CpG8 in the promoter region of HIF1α, showed marginally significant hypomethylation in preterm preeclampsia compared to controls ( β = − 0.15%, p = 0.055). HIF1α expression was significantly lower in preterm preeclampsia compared to controls (mean ± SE = 10.16 ± 2.00 vs 4.25 ± 0.90, p = 0.04). Further, DNAm in HIF1α promoter region was negatively associated with its expression levels ( β = − 0.165, p = 0.024). Several CpGs in HIF1α were negatively associated with placental weight and birth outcomes including birth weight ( β range = − 0.224–0.300) and birth length [ β range = − 0.248 to − 0.301 ( p < 0.05 for all)] . Overall, we demonstrate altered DNAm in HIF1α and HIF3α in preeclampsia placentae, also associated with various birth outcomes. Correlation of DNAm in HIF1α and its expression suggests a possible role in the pathogenesis of pre-eclampsia. Further investigations on interactions between HIF1α and HIF3α in preeclampsia would be interesting.