It has now been more than two years since we said our last goodbye to Jan Svoboda (14 [...].

• MeSH
• Humans MeSH
• Retroviridae classification   genetics   isolation & purification   physiology   MeSH
• Retroviridae Infections virology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH
• Introductory Journal Article MeSH
• Editorial MeSH

BACKGROUND: Syncytin-1 and 2, human fusogenic glycoproteins encoded by the env genes of the endogenous retroviral loci ERVWE1 and ERVFRDE1, respectively, contribute to the differentiation of multinucleated syncytiotrophoblast in chorionic villi. In non-trophoblastic cells, however, the expression of syncytins has to be suppressed to avoid potential pathogenic effects. Previously, we have shown that the transcriptional suppression of ERVWE1 promoter is controlled epigenetically by DNA methylation and chromatin modifications. In this study, we describe the aberrant expression of syncytin-1 in biopsies of testicular germ cell tumors. RESULTS: We found efficient expression and splicing of syncytin-1 in seminomas and mixed germ cell tumors with seminoma component. Although another fusogenic gene, syncytin-2 was also derepressed in seminomas, its expression was significantly lower than that of syncytin-1. Neither the transcription factor GCM1 nor the increased copy number of ERVWE1 were sufficient for this aberrant expression of syncytin-1 in seminomas. In accordance with our recent finding of the highly increased expression of TET1 dioxygenase in most seminomas, the ERVWE1 promoter was significantly hypomethylated in comparison with the matched controls. In contrast, 5-hydroxymethylcytosine levels were not detectable at the ERVWE1 promoter. We further describe that another endogenous retroviral element adjacent to ERVWE1 remains transcriptionally suppressed and two additional HERV-W family members are only slightly upregulated in seminomas. CONCLUSIONS: We conclude that DNA demethylation of the ERVWE1 promoter in seminomas is a prerequisite for syncytin-1 derepression. We propose the spliced syncytin-1 expression as a marker of seminoma and suggest that aberrant expression of endogenous retroviruses might be a correlate of the hypomethylated genome of seminomas.

• Keywords
• 5-Hydroxymethylcytosine, ERVWE1, Germ cell tumor, Human endogenous retrovirus, Promoter DNA methylation, RNA splicing, Seminoma, Transcription,
• MeSH
• DNA, Viral metabolism   MeSH
• Endogenous Retroviruses genetics   MeSH
• Epigenesis, Genetic MeSH
• Gene Products, env biosynthesis   MeSH
• Humans MeSH
• DNA Methylation MeSH
• Gene Expression Regulation * MeSH
• Seminoma pathology   virology   MeSH
• Pregnancy Proteins biosynthesis   MeSH
• Testicular Neoplasms pathology   virology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• DNA, Viral MeSH
• Gene Products, env MeSH
• syncytin MeSH Browser
• Pregnancy Proteins MeSH

Syncytin-1 and -2, human fusogenic glycoproteins encoded by the env genes of the endogenous retroviral loci ERVWE1 and ERVFRDE1, respectively, contribute to the differentiation of multinucleated syncytiotrophoblast in chorionic villi. In non-trophoblastic cells, however, the expression of syncytins has to be suppressed to avoid potential pathogenic effects. We studied the epigenetic suppression of ERVWE1 and ERVFRDE1 5'-long terminal repeats by DNA methylation and chromatin modifications. Immunoprecipitation of the provirus-associated chromatin revealed the H3K9 trimethylation at transcriptionally inactivated syncytins in HeLa cells. qRT-PCR analysis of non-spliced ERVWE1 and ERVFRDE1 mRNAs and respective env mRNAs detected efficient splicing of endogenously expressed RNAs in trophoblastic but not in non-placental cells. Pointing to the pathogenic potential of aberrantly expressed syncytin-1, we have found deregulation of transcription and splicing of the ERVWE1 in biopsies of testicular seminomas. Finally, ectopic expression experiments suggest the importance of proper chromatin context for the ERVWE1 splicing. Our results thus demonstrate that cell-specific retroviral splicing represents an additional epigenetic level controling the expression of endogenous retroviruses.

• MeSH
• Cell Line MeSH
• Endogenous Retroviruses * MeSH
• Epigenesis, Genetic * MeSH
• Transcription, Genetic * MeSH
• Gene Products, env genetics   metabolism   MeSH
• Neoplasms, Germ Cell and Embryonal genetics   metabolism   MeSH
• Glycoproteins genetics   metabolism   MeSH
• HeLa Cells MeSH
• Histones metabolism   MeSH
• Humans MeSH
• RNA, Messenger metabolism   MeSH
• Proviruses genetics   metabolism   MeSH
• RNA Splicing * MeSH
• Pregnancy Proteins genetics   metabolism   MeSH
• Testis metabolism   MeSH
• Gene Silencing MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• ERVFRD-1 protein, human MeSH Browser
• Gene Products, env MeSH
• Glycoproteins MeSH
• Histones MeSH
• RNA, Messenger MeSH
• syncytin MeSH Browser
• Pregnancy Proteins MeSH