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Journal of Virology, January 2005, p. 876-883, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.876-883.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Laurence Lavie,{dagger} Milena Kitova,{dagger} 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.

* Corresponding author. Mailing address: Department of Human Genetics, Building 60, University of Saarland, Medical Faculty, 66421 Hamburg, Germany. Phone: 49 6841 1626627. Fax: 49 6841 1626186. E-mail: jens.mayer{at}uniklinik-saarland.de.

{dagger} L.L. and M.K. made equal contributions.

Journal of Virology, January 2005, p. 876-883, Vol. 79, No. 2
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.2.876-883.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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