Reduced syncytin-1 expression levels in placental syndromes correlates with epigenetic hypermethylation of the ERVW-1 promoter region

• Published in: PloS one Vol. 8; no. 2; p. e56145
• Main Authors: Ruebner, Matthias, Strissel, Pamela L, Ekici, Arif B, Stiegler, Elisabeth, Dammer, Ulf, Goecke, Tamme W, Faschingbauer, Florian, Fahlbusch, Fabian B, Beckmann, Matthias W, Strick, Reiner
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14-02-2013; Public Library of Science (PLoS)
• Subjects: Aberration; Apoptosis; Biology; Biotechnology; Cancer; Cell adhesion & migration; Cell fusion; Cell Line; Cell lines; Demethylation; Deoxyribonucleic acid; Disorders; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA - genetics; DNA Helicases - genetics; DNA Methylation; Down-Regulation; Env gene; Enzymes; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Female; Fetuses; Gene expression; Gene Products, env - genetics; Genes; Genomes; Gynecology; Humans; Kinases; Laboratories; Liver; Maternal effects; Medicine; Methylation; Methyltransferases; Morphology; Obstetrics; Placenta; Placenta - metabolism; Placenta - pathology; Platelets; Pre-eclampsia; Pregnancy; Pregnancy Proteins - genetics; Promoter Regions, Genetic; Proteins; RNA polymerase; Stem cells; Syncytin; Tumors; Up-Regulation; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056145

Terminal differentiation of villous cytotrophoblasts (CT) ends in formation of the multinucleated syncytiotrophoblast representing the fetal-maternal interface. Aberrations during this cell-fusion process are associated with Intrauterine Growth Restriction (IUGR), Preeclampsia (PE) and High Elevated Liver and Low Platelets (HELLP) Syndrome. Syncytin-1, the envelope gene of the human Endogenous Retrovirus ERVW-1, is one of the most important genes involved in cell-fusion and showed decreased gene expression during these pathological pregnancies. The aim of this study was to determine the methylation pattern of the entire promoter of ERVW-1 and to correlate these findings with the expression profile of Syncytin-1 in the placental syndromes. 14 isolated villous cytotrophoblasts from control (n = 3), IUGR (n = 3), PE (n = 3), PE/IUGR (n = 3) and HELLP/IUGR (n = 2) placentae were used to determine the mean methylation level (ML) for the ERVW-1 promoter region. ML rose significantly from 29% in control CTs to 49% in IUGR, 53% in PE, 47% in PE/IUGR and 64% in HELLP/IUGR indicating an epigenetic down-regulation of Syncytin-1 by promoter hypermethylation. DNA demethylation of the trophoblast like cell lines BeWo, JEG-3 and JAR with 5-AZA-2'desoxycytidine (AZA) showed an increased Syncytin-1 expression and fusion ability in all cell lines. Promoter activity of the 5'LTR could be inhibited by hypermethylation 42-fold using a luciferase based reporter-gene assay. Finally overexpression of the methyltransferases DNMT3a and LSH could be responsible for a decreased Syncytin-1 expression by promoter hypermethylation of ERVW-1. Our study linked decreased Syncytin-1 expression to an epigenetic hypermethylation of the entire promoter of ERVW-1. Based on our findings we are predicting a broad aberrant epigenetic DNA-methylation pattern in pathological placentae affecting placentogenesis, but also the development of the fetus and the mother during pregnancy.