title: Reduced syncytin-1 expression levels in placental syndromes correlates with epigenetic hypermethylation of the ERVW-1 promoter region.
abstract: 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.
authors: University-Clinic Erlangen, Department of Gynaecology and Obstetrics, Laboratory for Molecular Medicine, Erlangen, Germany. Matthias.Ruebner@uk-erlangen.de
authors: Matthias
authors: M
authors: Ruebner
authors: Pamela L
authors: PL
authors: Strissel
authors: Arif B
authors: AB
authors: Ekici
authors: Elisabeth
authors: E
authors: Stiegler
authors: Ulf
authors: U
authors: Dammer
authors: Tamme W
authors: TW
authors: Goecke
authors: Florian
authors: F
authors: Faschingbauer
authors: Fabian B
authors: FB
authors: Fahlbusch
authors: Matthias W
authors: MW
authors: Beckmann
authors: Reiner
authors: R
authors: Strick
mesh_terms: D002460:Cell Line; D004247:DNA / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005260:Female; D015686:Gene Products, env / Q000235:genetics*; D006801:Humans; D010920:Placenta / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D015854:Up-Regulation
chemical_list: C000717967:DNMT3A protein, human; D015686:Gene Products, env; D011257:Pregnancy Proteins; C405335:syncytin; D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D004265:DNA Helicases; C412063:HELLS protein, human