The Role of Epigenetics in Placental Development and the Etiology of Preeclampsia

Abstract

In this review, we comprehensively present the function of epigenetic regulations in normal placental development as well as in a prominent disease of placental origin, preeclampsia (PE). We describe current progress concerning the impact of DNA methylation, non-coding RNA (with a special emphasis on long non-coding RNA (lncRNA) and microRNA (miRNA)) and more marginally histone post-translational modifications, in the processes leading to normal and abnormal placental function. We also explore the potential use of epigenetic marks circulating in the maternal blood flow as putative biomarkers able to prognosticate the onset of PE, as well as classifying it according to its severity. The correlation between epigenetic marks and impacts on gene expression is systematically evaluated for the different epigenetic marks analyzed.

Keywords: DNA methylation; H19; HOX genes; epigenetics; histone post translational modifications; miR-210; miRNAs; non coding RNAs; preeclampsia.

Figure 1

(A) Blastocyst implantation and Placenta Development: After recognizing the uterine lining, the blastocyst is formed by the embryoblast (EB) and the cytotrophoblast (CT). The cytotrophoblast starts to differentiate into Synctiotrophoblast (SCT). SCT invades the endometrium towards the maternal spiral arteries located in the myometrium. deregulation of numerous genes is observed [19]. Lacunae develop in the syncytiotrophoblast, which will eventually constitute the intervillous space. Genes upregulated during villi formation are presented on the right figure [20]. Other cytotrophoblasts will invade the maternal spiral arteries by differentiating into Extravillous trophoblast. (B) Gene Ontology of genes differentially methylated in PE compared to control samples: (Left) in normal pregnancies, extravillous trophoblast (EVT) invades the maternal spiral arteries allowing for an increased blood stream towards the extravillous space. Nutrients cross the placenta, are directed towards the embryonic vessels and collected in the umbilical cord. In PE, decreased invasion of the EVTs induces poor spiral artery remodeling, leading to poor blood flow towards the placenta. Increased amount of microparticles from the syncytiotrophoblast and increased amount of free fetal DNA is observed in the maternal blood. (Right) Gene ontology of differentially methylated genes found in PE samples in different tissues affected during pregnancy: Umbilical cord, placenta, EVT, Endothelial Maternal cells (see text for detail).

Figure 2

Overview of the molecular mechanisms at play in preeclampsia. Annotations: eNOS = Endothelial Nitric Oxide Synthase; EZH2 = Enhancer of Zeste Homolog 2; FOXP3 = Forkhead box P3; IGF-1 = Insuline-like Growth Factor 1; ISCU = Iron-sulfur cluster; Lnc-DC = Long non-coding RNA DC; miR-30a-5p = microRNA 30a-5p; miR-155 = micro-RNA 155; miR-210 = microRNA 210; MMP-9 = Matrix Metalloproteinase-9; NO = Nitric Oxide; RND3 = Rho Family GTPase 3; ROS = Reactive Oxygen Species; sENG = Soluble endoglin; sFLT1 = Soluble fms-like tyrosine kinase receptor-1; STAT3 = Signal transducer and activator of transcription 3; STOX1 = Storkhead Box 1; TET2 = Tet methylcytosine dioxygenase 2; TIMP3 = TIMP Metallopeptidase Inhibitor 3; TUG1 = long non-coding RNA taurine-upregulated gene 1; VEGF = Vascular Endothelial Growth Factor.

Figure 3

Overview of major methylation alterations in preeclampsia. The main pathways are shown in green boxes. The significant alterations in methylation may be associated either to increased or decreased gene expression (hypermethylated in red and hypomethylated in blue).