CpG methylation directly regulates transcriptional activity of the human endogenous retrovirus family HERV-K(HML-2).
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.
Lavie
Laurence
L
Department of Human Genetics, Building 60, University of Saarland, Medical Faculty, 66421 Hamburg, Germany. jens.mayer@uniklinik-saarland.de.
Kitova
Milena
M
Maldener
Esther
E
Meese
Eckart
E
Mayer
Jens
J
D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D020077:Endogenous Retroviruses / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic; D020079:Terminal Repeat Sequences; D014158:Transcription, Genetic