This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lavie, L. Articles by Mayer, J. Search for Related Content PubMed PubMed Citation Articles by Lavie, L. Articles by Mayer, J.

CpG Methylation Directly Regulates Transcriptional Activity of the Human Endogenous Retrovirus Family HERV-K(HML-2)

Laurence Lavie, Milena Kitova, Esther Maldener, Eckart Meese, and Jens Mayer^*

Department of Human Genetics, University of Saarland, Hamburg, Germany

Received 23 June 2004/ Accepted 12 August 2004

A significant proportion of the human genome consists of stably inherited retroviral sequences. Most human endogenous retroviruses (HERVs) became defective over time. The HERV-K(HML-2) family is exceptional because of its coding capacity and the possible involvement in germ cell tumor (GCT) development. HERV-K(HML-2) transcription is strongly upregulated in GCTs. However, regulation of HERV-K(HML-2) transcription remains poorly understood. We investigated in detail the role of CpG methylation on the transcriptional activity of HERV-K(HML-2) long terminal repeats (LTRs). We find that CpG sites in various HERV-K(HML-2) proviral 5' LTRs are methylated at different levels in the cell line Tera-1. Methylation levels correlate with previously observed transcriptional activities of these proviruses. CpG-mediated silencing of HERV-K(HML-2) LTRs is further corroborated by transcriptional inactivity of in vitro-methylated 5' LTR reporter plasmids. However, CpG methylation levels do not solely regulate HERV-K(HML-2) 5' LTR activity, as evidenced by different LTR activities in the cell line T47D. A significant number of mutated CpG sites in evolutionary old HERV-K(HML-2) 5' LTRs suggests that CpG methylation had already silenced HERV-K(HML-2) proviruses millions of years ago. Direct silencing of HERV-K(HML-2) expression by CpG methylation enlightens upregulated HERV-K(HML-2) expression in usually hypomethylated GCT tissue.

L.L. and M.K. made equal contributions.

This article has been cited by other articles:

• Voisset, C., Weiss, R. A., Griffiths, D. J. (2008). Human RNA "Rumor" Viruses: the Search for Novel Human Retroviruses in Chronic Disease. Microbiol. Mol. Biol. Rev. 72: 157-196 [Abstract] [Full Text]  
• Frank, O., Verbeke, C., Schwarz, N., Mayer, J., Fabarius, A., Hehlmann, R., Leib-Mosch, C., Seifarth, W. (2008). Variable Transcriptional Activity of Endogenous Retroviruses in Human Breast Cancer. J. Virol. 82: 1808-1818 [Abstract] [Full Text]  
• Garrison, B. S., Yant, S. R., Mikkelsen, J. G., Kay, M. A. (2007). Postintegrative Gene Silencing within the Sleeping Beauty Transposition System. Mol. Cell. Biol. 27: 8824-8833 [Abstract] [Full Text]  
• Kashkush, K., Khasdan, V. (2007). Large-Scale Survey of Cytosine Methylation of Retrotransposons and the Impact of Readout Transcription From Long Terminal Repeats on Expression of Adjacent Rice Genes. Genetics 177: 1975-1985 [Abstract] [Full Text]  
• Reiss, D., Zhang, Y., Mager, D. L. (2007). Widely variable endogenous retroviral methylation levels in human placenta. Nucleic Acids Res 35: 4743-4754 [Abstract] [Full Text]  
• Dewannieux, M., Harper, F., Richaud, A., Letzelter, C., Ribet, D., Pierron, G., Heidmann, T. (2006). Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements. Genome Res. 16: 1548-1556 [Abstract] [Full Text]  
• Buzdin, A., Kovalskaya-Alexandrova, E., Gogvadze, E., Sverdlov, E. (2006). At Least 50% of Human-Specific HERV-K (HML-2) Long Terminal Repeats Serve In Vivo as Active Promoters for Host Nonrepetitive DNA Transcription.. J. Virol. 80: 10752-10762 [Abstract] [Full Text]  
• Esnault, C., Millet, J., Schwartz, O., Heidmann, T. (2006). Dual inhibitory effects of APOBEC family proteins on retrotransposition of mammalian endogenous retroviruses. Nucleic Acids Res 34: 1522-1531 [Abstract] [Full Text]  
• Maksakova, I. A., Mager, D. L. (2005). Transcriptional Regulation of Early Transposon Elements, an Active Family of Mouse Long Terminal Repeat Retrotransposons. J. Virol. 79: 13865-13874 [Abstract] [Full Text]  
• Frank, O., Giehl, M., Zheng, C., Hehlmann, R., Leib-Mosch, C., Seifarth, W. (2005). Human Endogenous Retrovirus Expression Profiles in Samples from Brains of Patients with Schizophrenia and Bipolar Disorders. J. Virol. 79: 10890-10901 [Abstract] [Full Text]