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

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

doi:10.1186/1471-2164-9-354

Cited by 99 publications

(125 citation statements)

References 72 publications

Supporting

Mentioning

118

Contrasting

Order By: Relevance

“…Subregions of the alignment were used for further analyses. The sequence assignment strategy and the Locus-Assigner software were previously discussed in more detail (19). cDNA sequences with more than 17 mismatches to the bestmatching reference proviral sequence were excluded from further analysis because they very likely represent recombined cDNAs from different proviral transcripts that arose ex vivo during cDNA generation (18).…”

Section: Methodsmentioning

confidence: 99%

Human Endogenous Retrovirus Family HERV-K(HML-2) RNA Transcripts Are Selectively Packaged into Retroviral Particles Produced by the Human Germ Cell Tumor Line Tera-1 and Originate Mainly from a Provirus on Chromosome 22q11.21

Ruprecht

Ferreira

Flockerzi

et al. 2008

J Virol

Self Cite

View full text Add to dashboard Cite

The human germ cell tumor line Tera-1 produces retroviral particles which are encoded by the human endogenous retrovirus family HERV-K(HML-2). We show here, by quantitative reverse transcriptase PCR, that HML-2 gag and env RNA transcripts are selectively packaged into Tera-1 retroviral particles, whereas RNAs from cellular housekeeping genes and from other HERV families (HERV-H and HERV-W) are nonselectively copackaged. Assignment of cloned HML-2 gag and env cDNAs from Tera-1 retroviral particles to individual HML-2 loci in the human genome demonstrated that HML-2 RNA transcripts packaged into Tera-1 retroviral particles originate almost exclusively from an HML-2 provirus on chromosome 22q11.21. Based on relative cloning frequencies, this provirus was the most active among a total of eight transcribed HML-2 loci identified in Tera-1 cells. These data suggest that at least one HML-2 element, that is, the HML-2 provirus on 22q11.21, has retained the capacity for packaging RNA into HML-2-encoded retroviral particles. Given its elevated transcriptional activity and the presence of a full-length Gag open reading frame, the 22q11.21 HML-2 provirus may also significantly contribute to Gag protein and thus particle production in Tera-1 cells. Our findings provide important clues to the generation and biological properties of HML-2-encoded particles. In addition, copackaging of non-HML-2 HERV transcripts in HML-2-encoded particles should inform the debate about endogenous retroviral particles putatively encoded by non-HML-2 HERV families that have previously been described for other human diseases, such as multiple sclerosis.

show abstract

Section: Methodsmentioning

confidence: 99%

Human Endogenous Retrovirus Family HERV-K(HML-2) RNA Transcripts Are Selectively Packaged into Retroviral Particles Produced by the Human Germ Cell Tumor Line Tera-1 and Originate Mainly from a Provirus on Chromosome 22q11.21

Ruprecht

Ferreira

Flockerzi

et al. 2008

J Virol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although not interchangeable, rec is a functional homologue of the HIV rev, human T-cell leukemia virus (HTLV) rex, and mouse mammary tumor virus (MMTV) rem genes. rec has been deleted in most of the HERV-K elements (type 1 proviruses) but is present in the majority of the youngest humanspecific integrants (type 2 proviruses) (11,18). Although they are repressed in somatic tissues, HERV-K proteins are reexpressed in certain tumors, most prominently germ cell tumors (GCTs) and melanomas.…”

mentioning

confidence: 99%

Expression of the Human Endogenous Retrovirus (HERV) Group HML-2/HERV-K Does Not Depend on Canonical Promoter Elements but Is Regulated by Transcription Factors Sp1 and Sp3

Fuchs

Kraft

Tondera

et al. 2011

J Virol

View full text Add to dashboard Cite

After fixation in the human genome, human endogenous retroviruses (HERVs) are bona fide cellular genes despite their exogenous origin. To be able to spread within the germ line and the early embryo, the ancient retroviral promoters must have adapted to the requirements for expression in these cell types. We describe that in contrast to the case for current exogenous retroviruses, which replicate in specific somatic cells, the long terminal repeat (LTR) of the human endogenous retrovirus HERV-K acts as a TATA-and initiator elementindependent promoter with a variable transcription start site. We present evidence that the HERV-K LTR is regulated by the transcription factors Sp1 and Sp3. Mutating specific GC boxes, which are binding sites for Sp proteins, and knocking down Sp1 and Sp3 by use of small interfering RNA (siRNA) significantly reduced the promoter activity. Binding of Sp1 and Sp3 to the promoter region was confirmed using electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP). Our data explain why certain HERV-K proviruses have lost promoter competence. Since vertebrate promoters lacking canonical core promoter elements are common but poorly studied, understanding the HERV-K promoter not only will provide insight into the regulation of endogenous retroviruses but also can serve as a paradigm for understanding the regulation of this class of cellular genes.Human endogenous retroviruses (HERVs) bear witness that during primate/human evolution exogenous retroviruses have repetitively infected and colonized the germ lines of their respective hosts. HERV sequences constitute approximately 8% of the human genome. However, all present-day proviral loci in the human lineage are rendered noninfectious by mutations and deletions, probably through genetic drift and-given the mutagenic potential of retroviruses-selection for replicationincompetent proviruses. In addition, detailed in silico analyses showed that several HERV proviruses are already inactivated during the primary infection cycle by an APOBEC3G cytosine deaminase, an antiretroviral gene which leaves specific mutation marks within the proviral DNA (17, 33).

show abstract

“…Additionally, PCR amplifications using highly degenerated primers coupled with low density microarrays intended to detect and quantify the expression of HERV families 27,28 . In order to trace the expression of individual locus within a family, approaches based on the PCR amplification of conserved regions combined with subsequent cloning and sequencing enabled transcriptionally active distinct elements of the HML-2 29,30 or HERV-E4.1 31 families to be identified. Also ending by cloning and sequencing steps, the genome repeat expression monitoring technique aiming to identify promoters among repeats identified active HML-2 specific human solitary LTRs 32,33 .…”

Section: Discussionmentioning

confidence: 99%

Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer

Pérot¹,

Cheynet²,

Decaussin‐Petrucci³

et al. 2013

JoVE

View full text Add to dashboard Cite

The prostate-specific antigen (PSA) is the main diagnostic biomarker for prostate cancer in clinical use, but it lacks specificity and sensitivity, particularly in low dosage values 1 . 'How to use PSA' remains a current issue, either for diagnosis as a gray zone corresponding to a concentration in serum of 2.5-10 ng/ml which does not allow a clear differentiation to be made between cancer and noncancer 2 or for patient follow-up as analysis of post-operative PSA kinetic parameters can pose considerable challenges for their practical application 3,4 . Alternatively, noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease, e.g. PCA3 in prostate cancer 5,6 and to reveal uncharacterized aspects of tumor biology. Moreover, data from the ENCODE project published in 2012showed that different RNA types cover about 62% of the genome. It also appears that the amount of transcriptional regulatory motifs is at least 4.5x higher than the one corresponding to protein-coding exons. Thus, long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) constitute a wide range of putative/candidate transcriptional regulatory sequences, as it is their primary function in infectious retroviruses. HERVs, which are spread throughout the human genome, originate from ancestral and independent infections within the germ line, followed by copy-paste propagation processes and leading to multicopy families occupying 8% of the human genome (note that exons span 2% of our genome). Some HERV loci still express proteins that have been associated with several pathologies including cancer [7][8][9][10]

show abstract

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

Cited by 99 publications

References 72 publications

Human Endogenous Retrovirus Family HERV-K(HML-2) RNA Transcripts Are Selectively Packaged into Retroviral Particles Produced by the Human Germ Cell Tumor Line Tera-1 and Originate Mainly from a Provirus on Chromosome 22q11.21

Human Endogenous Retrovirus Family HERV-K(HML-2) RNA Transcripts Are Selectively Packaged into Retroviral Particles Produced by the Human Germ Cell Tumor Line Tera-1 and Originate Mainly from a Provirus on Chromosome 22q11.21

Expression of the Human Endogenous Retrovirus (HERV) Group HML-2/HERV-K Does Not Depend on Canonical Promoter Elements but Is Regulated by Transcription Factors Sp1 and Sp3

Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer

Contact Info

Product

Resources

About