title: Decreased expression and altered methylation of syncytin-1 gene in human placentas associated with preeclampsia.
abstract: Syncytin-1 is a protein coded by a human endogenous retrovirus (HERV) gene of the HERV-W family (HERVWE1). Syncytin- 1 mediates formation of syncytiotrophoblasts through fusion of cytotrophoblasts, a hallmark of terminal differentiation of placental trophoblast linage. Syncytin-1 also possesses nonfusogenic functions and regulates cell cycle progression. While decreased syncytin-1 expression and syncytium deficiency are considered important pathological changes in preeclampsia, the molecular mechanism(s) underlying syncytin-1 downregulation remains unclear. In this study, we confirmed that expression levels of syncytin-1 mRNA and protein were significantly lower in preeclamptic placentas compared to normal controls. Human chorionic somatomammotropin expression, a marker for syncytium function, was also decreased in preeclamptic placentas. The mRNA levels of ASCT2, the syncytin-1 receptor involved in cell fusion process, and GCMa, a transcriptional factor known to regulate syncytin-1 expression, were not significantly altered. Methylation in the 5'LTR of syncytin-1 promoter was quantified by COBRA, methylation-specific PCR, and DNA sequencing. Results from all three assays indicated significantly hypermethylated syncytin-1 promoter in preeclamptic placentas compared to normal controls. Methylation levels were inversely correlated with syncytin-1 mRNA levels, suggesting that hypermethylation may lead to syncytin-1 downregulation. Further experiments indicated that DNMT1 and DNMT3B3 mRNA and protein levels were increased in preeclamptic placentas, suggesting that higher DNA methyltransferase activity may contribute to the hypermethylation of syncytin-1 in preeclamptic placentas. These results indicated that aberrant hypermethylation is involved in downregulation of syncytin-1, and epigenetic alterations may play a significant role in the development of preeclampsia.
authors.forename: Xue-Wei
authors.initials: XW
authors.lastname: Zhuang
authors.forename: Jinping
authors.initials: J
authors.lastname: Li
authors.forename: Brian C
authors.initials: BC
authors.lastname: Brost
authors.forename: Xi-Yan
authors.initials: XY
authors.lastname: Xia
authors.forename: Hai Bin
authors.initials: HB
authors.lastname: Chen
authors.forename: Chuan-Xin
authors.initials: CX
authors.lastname: Wang
authors.affiliation: Department of Biomedical Sciences, Mercer University School of Medicine, 4700 Waters Avenue, Savannah, GA 31404, USA. jiang_s@mercer.edu.
authors.forename: Shi-Wen
authors.initials: SW
authors.lastname: Jiang
mesh_terms: D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D020077:Endogenous Retroviruses / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015686:Gene Products, env / Q000235:genetics*; D006801:Humans; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000235:genetics*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014327:Trophoblasts / Q000378:metabolism
chemical_list: D015686:Gene Products, env; D011257:Pregnancy Proteins; D012333:RNA, Messenger; C405335:syncytin; D004248:DNA (Cytosine-5-)-Methyltransferases