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DNA methylation studies of preeclampsia and related conditions Blair, John

Abstract

Preeclampsia is a leading cause of maternal and fetal death throughout the world. It is caused by placental dysfunction and clinically characterized by hypertension and other adverse outcomes. Early-onset preeclampsia (EOPET) is a severe form of the disorder. Despite much investigation, the underlying biology of EOPET is unclear. It is known that disrupted oxygen delivery and altered cellular differentiation are characteristics of preeclampsia placentas, and that this likely has an effect on the placental molecular profile. This thesis primarily investigates DNA methylation, a key component in regulating gene expression, in placentas and cellular states related to EOPET. Investigating placental cells exposed to hypoxia, we found 147 CpG sites in cytotrophoblast whose DNA methylation was significantly altered by exposure to hypoxia for 24 hours. Many of these sites overlapped with the 223 CpG sites that were altered between normoxic cytotrophoblast and syncitiotrophoblast, however the change was in the opposite direction (hypomethylated vs. hypermethylated), implying hypoxia can molecularly prevent differentiation in trophoblast cells. Expanding on these findings to look at DNA methylation in placental tissue from preeclampsia pregnancies, we found significant differences at 282 CpG sites. Several of these differences occurred in genes that have functional relevance for the development of EOPET. Many of the candidate genes also showed differential gene expression in preeclampsia placentas. To investigate the utility of these candidate CpGs as 1st trimester EOPET biomarkers, placentas with increased susceptibility to preeclampsia (trisomy 16) were investigated across gestational ages. There were many DNA methylation differences in 3rd trimester trisomy 16 placentas that were shared with chromosomally normal 3rd trimester EOPET placentas, suggesting a common molecular profile of preeclampsia prone placentas, regardless of etiology. Comparing 1st trimester trisomy 16 against 3rd trimester trisomy 16, we found 77 CpG sites differentially methylated in both conditions, and further found 3 changes in first trimester trisomy 16 shared with 3rd trimester EOPET. Overall, these studies have identified several molecular changes in EOPET and related conditions that provide insight into the biology of the disorder while also providing novel candidates to investigate further in a clinical setting.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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