Expression patterns of transcribed human endogenous retrovirus HERV-K(HML-2) loci in human tissues and the need for a HERV Transcriptome Project

Aline Flockerzi,Marlies Sauter,Jens Mayer,Oliver Frank,Alessia Ruggieri,Bernd Wullich,Bernd Kopper,Christine Leib-Mösch,Esther Maldener,Nikolaus Müller-Lantzsch,Wolfgang Seifarth,Eckart Meese

doi:10.1186/1471-2164-9-354

Abstract

BackgroundA significant proportion of the human genome is comprised of human endogenous retroviruses (HERVs). HERV transcripts are found in every human tissue. Expression of proviruses of the HERV-K(HML-2) family has been associated with development of human tumors, in particular germ cell tumors (GCT). Very little is known about transcriptional activity of individual HML-2 loci in human tissues, though.ResultsBy employing private nucleotide differences between loci, we assigned ~1500 HML-2 cDNAs to individual HML-2 loci, identifying, in total, 23 transcriptionally active HML-2 proviruses. Several loci are active in various human tissue types. Transcription levels of some HML-2 loci appear higher than those of other loci. Several HML-2 Rec-encoding loci are expressed in GCT and non-GCT tissues. A provirus on chromosome 22q11.21 appears strongly upregulated in pathologic GCT tissues and may explain high HML-2 Gag protein levels in GCTs. Presence of Gag and Env antibodies in GCT patients is not correlated with activation of individual loci. HML-2 proviruses previously reported capable of forming an infectious HML-2 variant are transcriptionally active in germ cell tissue. Our study furthermore shows that Expressed Sequence Tag (EST) data are insufficient to describe transcriptional activity of HML-2 and other HERV loci in tissues of interest.ConclusionOur, to date, largest-scale study reveals in greater detail expression patterns of individual HML-2 loci in human tissues of clinical interest. Moreover, large-scale, specialized studies are indicated to better comprehend transcriptional activity and regulation of HERVs. We thus emphasize the need for a specialized HERV Transcriptome Project.

Highlights

A significant proportion of the human genome is comprised of human endogenous retroviruses (HERVs)
Generation of HML-2 cDNA sequences We analyzed, in total, 49 samples derived from tumor and normal tissues that were of higher interest because of various previous findings
We investigated in the present study in more detail normal and pathologic germ cell tissue because of the association of HML-2 with germ cell tumors (GCT) [1,32], and brain tissues because of previous results indicating transcriptional differences between tissue samples from patients with neuropsychiatric disorders [56]

Summary

Introduction

A significant proportion of the human genome is comprised of human endogenous retroviruses (HERVs). The human genome harbors a significant amount of sequences that stem from retroviral infections of the germ line in evolutionarily ancient times, so-called human endogenous retroviruses (HERVs). Many of the integrated retroviruses (proviruses) became defective due to accumulation of nonsense mutations, large internal deletions, or reduction to so-called solitary LTRs after homologous recombination within a provirus [for reviews, see [1,2,3,4]] Since proviruses carry their own transcriptional promoters and regulators within the Long Terminal Repeats (LTRs), HERV sequences are able to initiate transcription of the proviral gag, pro, pol and env genes, and to initiate transcription of neighboring cellular genes. Recent studies demonstrated that there is virtually no human tissue that lacks HERV transcripts, and transcripts from several HERV families are usually found in every investigated human tissue [13,14]

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