1887

Abstract

Marek’s disease virus (GaHV-2) is an alphaherpesvirus that induces T-cell lymphoma in chickens. The infection includes both lytic and latent stages. GaHV-2 encodes three clusters of microRNAs (miRNAs) located in the internal (I)/terminal (T) repeat (R) regions. We characterized transcripts encompassing the mdv1-mir-M9–M4 and mir-M11–M1 clusters located in the IR/TR region, upstream and downstream from the oncogene, respectively. By 5′- and 3′-RACE-PCR and targeted RT-PCR, we showed that mdv1-mir-M9–M4 could be transcribed from an unspliced transcript or from at least 15 alternatively spliced transcripts covering the IR/TR region, encompassing the and genes and localizing the mdv1-mir-M9–M4 cluster to the first intron at the 5′-end. However, all these transcripts, whether spliced or unspliced, seemed to start at the same transcriptional start site, their transcription being driven by a single promoter, prmiRM9M4. We demonstrated alternative promoter usage for the and genes, depending on the phase of GaHV-2 infection. During the latent phase, the prmiRM9M4 promoter drove transcription of the and genes and the mdv1-mir-M9–M4 cluster in the first intron of the corresponding transcripts. By contrast, during the lytic phase, this promoter drove the transcription only of the mdv1-mir-M9–M4 cluster to generate unspliced mRNA, the and genes being transcribed principally from their own promoters. Despite the expression of and the mdv1-mir-M9–M4 cluster under two different transcriptional processes during the latent and lytic phases, our data provide an explanation for expression and mdv1-mir-M4-5P overexpression in miRNA libraries from GaHV-2-infected cells, regardless of the phase of infection.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.040741-0
2012-07-01
2020-11-30
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/7/1519.html?itemId=/content/journal/jgv/10.1099/vir.0.040741-0&mimeType=html&fmt=ahah

References

  1. Akiyama Y., Kato S., Iwa N. 1973; Continuous cell culture from lymphoma of Marek’s disease. Biken J 16:177–179[PubMed]
    [Google Scholar]
  2. Anobile J. M., Arumugaswami V., Downs D., Czymmek K., Parcells M., Schmidt C. J. 2006; Nuclear localization and dynamic properties of the Marek’s disease virus oncogene products Meq and Meq/vIL8. J Virol 80:1160–1166 [CrossRef][PubMed]
    [Google Scholar]
  3. Borchert G. M., Lanier W., Davidson B. L. 2006; RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol 13:1097–1101 [CrossRef][PubMed]
    [Google Scholar]
  4. Bradley G., Hayashi M., Lancz G., Tanaka A., Nonoyama M. 1989; Structure of the Marek’s disease virus BamHI-H gene family: genes of putative importance for tumor induction. J Virol 63:2534–2542[PubMed]
    [Google Scholar]
  5. Brown A. C., Nair V., Allday M. J. 2012; Epigenetic regulation of the latency-associated region of Marek’s disease virus in tumor-derived T-cell lines and primary lymphoma. J Virol 86:1683–1695[PubMed] [CrossRef]
    [Google Scholar]
  6. Burnside J., Bernberg E., Anderson A., Lu C., Meyers B. C., Green P. J., Jain N., Isaacs G., Morgan R. W. 2006; Marek’s disease virus encodes microRNAs that map to meq and the latency-associated transcript. J Virol 80:8778–8786 [CrossRef][PubMed]
    [Google Scholar]
  7. Burnside J., Ouyang M., Anderson A., Bernberg E., Lu C., Meyers B. C., Green P. J., Markis M., Isaacs G. other authors 2008; Deep sequencing of chicken microRNAs. BMC Genomics 9:185 [CrossRef][PubMed]
    [Google Scholar]
  8. Cai X., Cullen B. R. 2006; Transcriptional origin of Kaposi’s sarcoma-associated herpesvirus microRNAs. J Virol 80:2234–2242 [CrossRef][PubMed]
    [Google Scholar]
  9. Cui X., Lee L. F., Reed W. M., Kung H. J., Reddy S. M. 2004; Marek’s disease virus-encoded vIL-8 gene is involved in early cytolytic infection but dispensable for establishment of latency. J Virol 78:4753–4760 [CrossRef][PubMed]
    [Google Scholar]
  10. Davis B. N., Hata A. 2009; Regulation of microRNA biogenesis: a miRiad of mechanisms. Cell Commun Signal 7:18 [CrossRef][PubMed]
    [Google Scholar]
  11. Debba-Pavard M., Ait-Lounis A., Soubieux D., Rasschaert D., Dambrine G. 2008; Vaccination against Marek’s disease reduces telomerase activity and viral gene transcription in peripheral blood leukocytes from challenged chickens. Vaccine 26:4904–4912 [CrossRef][PubMed]
    [Google Scholar]
  12. Deng X., Li X., Shen Y., Qiu Y., Shi Z., Shao D., Jin Y., Chen H., Ding C. other authors 2010; The Meq oncoprotein of Marek’s disease virus interacts with p53 and inhibits its transcriptional and apoptotic activities. Virol J 7:348 [CrossRef][PubMed]
    [Google Scholar]
  13. Ding J., Cui Z., Lee L. F., Cui X., Reddy S. M. 2006; The role of pp38 in regulation of Marek’s disease virus bi-directional promoter between pp38 and 1.8-kb mRNA. Virus Genes 32:193–201 [CrossRef][PubMed]
    [Google Scholar]
  14. Fragnet L., Blasco M. A., Klapper W., Rasschaert D. 2003; The RNA subunit of telomerase is encoded by Marek’s disease virus. J Virol 77:5985–5996 [CrossRef][PubMed]
    [Google Scholar]
  15. Hong Y., Frame M., Coussens P. M. 1995; A 14-kDa immediate-early phosphoprotein is specifically expressed in cells infected with oncogenic Marek’s disease virus strains and their attenuated derivatives. Virology 206:695–700 [CrossRef][PubMed]
    [Google Scholar]
  16. Jarosinski K. W., Schat K. A. 2007; Multiple alternative splicing to exons II and III of viral interleukin-8 (vIL-8) in the Marek’s disease virus genome: the importance of vIL-8 exon I. Virus Genes 34:9–22 [CrossRef][PubMed]
    [Google Scholar]
  17. Jarosinski K. W., O’Connell P. H., Schat K. A. 2003; Impact of deletions within the BamHI-L fragment of attenuated Marek’s disease virus on vIL-8 expression and the newly identified transcript of open reading frame LORF4. Virus Genes 26:255–269 [CrossRef][PubMed]
    [Google Scholar]
  18. Jarosinski K. W., Osterrieder N., Nair V. K., Schat K. A. 2005; Attenuation of Marek’s disease virus by deletion of open reading frame RLORF4 but not RLORF5a. J Virol 79:11647–11659 [CrossRef][PubMed]
    [Google Scholar]
  19. Jones D., Lee L., Liu J. L., Kung H. J., Tillotson J. K. 1992; Marek’s disease virus encodes a basic-leucine zipper gene resembling the fos/jun oncogenes that is highly expressed in lymphoblastoid tumors. Proc Natl Acad Sci U S A 89:4042–4046 [CrossRef][PubMed]
    [Google Scholar]
  20. Jurak I., Kramer M. F., Mellor J. C., van Lint A. L., Roth F. P., Knipe D. M., Coen D. M. 2010; Numerous conserved and divergent microRNAs expressed by herpes simplex viruses 1 and 2. J Virol 84:4659–4672 [CrossRef][PubMed]
    [Google Scholar]
  21. Kaufer B. B., Trapp S., Jarosinski K. W., Osterrieder N. 2010; Herpesvirus telomerase RNA(vTR)-dependent lymphoma formation does not require interaction of vTR with telomerase reverse transcriptase (TERT). PLoS Pathog 6:e1001073 [CrossRef][PubMed]
    [Google Scholar]
  22. Lee Y., Kim M., Han J., Yeom K. H., Lee S., Baek S. H., Kim V. N. 2004; MicroRNA genes are transcribed by RNA polymerase II. EMBO J 23:4051–4060 [CrossRef][PubMed]
    [Google Scholar]
  23. Levy A. M., Izumiya Y., Brunovskis P., Xia L., Parcells M. S., Reddy S. M., Lee L., Chen H. W., Kung H. J. 2003; Characterization of the chromosomal binding sites and dimerization partners of the viral oncoprotein Meq in Marek’s disease virus-transformed T cells. J Virol 77:12841–12851 [CrossRef][PubMed]
    [Google Scholar]
  24. Liu J. L., Kung H. J. 2000; Marek’s disease herpesvirus transforming protein MEQ: a c-Jun analogue with an alternative life style. Virus Genes 21:51–64 [CrossRef][PubMed]
    [Google Scholar]
  25. Liu J. L., Ye Y., Lee L. F., Kung H. J. 1998; Transforming potential of the herpesvirus oncoprotein MEQ: morphological transformation, serum-independent growth, and inhibition of apoptosis. J Virol 72:388–395[PubMed]
    [Google Scholar]
  26. Liu J. L., Lin S. F., Xia L., Brunovskis P., Li D., Davidson I., Lee L. F., Kung H. J. 1999; MEQ and V-IL8: cellular genes in disguise?. Acta Virol 43:94–101[PubMed]
    [Google Scholar]
  27. Lupiani B., Lee L. F., Cui X., Gimeno I., Anderson A., Morgan R. W., Silva R. F., Witter R. L., Kung H. J., Reddy S. M. 2004; Marek’s disease virus-encoded Meq gene is involved in transformation of lymphocytes but is dispensable for replication. Proc Natl Acad Sci U S A 101:11815–11820 [CrossRef][PubMed]
    [Google Scholar]
  28. Monteys A. M., Spengler R. M., Wan J., Tecedor L., Lennox K. A., Xing Y., Davidson B. L. 2010; Structure and activity of putative intronic miRNA promoters. RNA 16:495–505 [CrossRef][PubMed]
    [Google Scholar]
  29. Morgan R., Anderson A., Bernberg E., Kamboj S., Huang E., Lagasse G., Isaacs G., Parcells M., Meyers B. C. other authors 2008; Sequence conservation and differential expression of Marek’s disease virus microRNAs. J Virol 82:12213–12220 [CrossRef][PubMed]
    [Google Scholar]
  30. Muylkens B., Coupeau D., Dambrine G., Trapp S., Rasschaert D. 2010; Marek’s disease virus microRNA designated Mdv1-pre-miR-M4 targets both cellular and viral genes. Arch Virol 155:1823–1837 [CrossRef][PubMed]
    [Google Scholar]
  31. Ohashi K., Zhou W., O’Connell P. H., Schat K. A. 1994; Characterization of a Marek’s disease virus BamHI-L-specific cDNA clone obtained from a Marek’s disease lymphoblastoid cell line. J Virol 68:1191–1195[PubMed]
    [Google Scholar]
  32. Osterrieder N., Kamil J. P., Schumacher D., Tischer B. K., Trapp S. 2006; Marek’s disease virus: from miasma to model. Nat Rev Microbiol 4:283–294 [CrossRef][PubMed]
    [Google Scholar]
  33. Parcells M. S., Lin S. F., Dienglewicz R. L., Majerciak V., Robinson D. R., Chen H. C., Wu Z., Dubyak G. R., Brunovskis P. other authors 2001; Marek’s disease virus (MDV) encodes an interleukin-8 homolog (vIL-8): characterization of the vIL-8 protein and a vIL-8 deletion mutant MDV. J Virol 75:5159–5173 [CrossRef][PubMed]
    [Google Scholar]
  34. Peng Q., Shirazi Y. 1996; Characterization of the protein product encoded by a splicing variant of the Marek’s disease virus Eco-Q gene (Meq). Virology 226:77–82 [CrossRef][PubMed]
    [Google Scholar]
  35. Peng Q., Zeng M., Bhuiyan Z. A., Ubukata E., Tanaka A., Nonoyama M., Shirazi Y. 1995; Isolation and characterization of Marek’s disease virus (MDV) cDNAs mapping to the BamHI-I2, BamHI-Q2, and BamHI-L fragments of the MDV genome from lymphoblastoid cells transformed and persistently infected with MDV. Virology 213:590–599 [CrossRef][PubMed]
    [Google Scholar]
  36. Pfeffer S., Sewer A., Lagos-Quintana M., Sheridan R., Sander C., Grässer F. A., van Dyk L. F., Ho C. K., Shuman S. other authors 2005; Identification of microRNAs of the herpesvirus family. Nat Methods 2:269–276 [CrossRef][PubMed]
    [Google Scholar]
  37. Reese T. A., Xia J., Johnson L. S., Zhou X., Zhang W., Virgin H. W. 2010; Identification of novel microRNA-like molecules generated from herpesvirus and host tRNA transcripts. J Virol 84:10344–10353 [CrossRef][PubMed]
    [Google Scholar]
  38. Ross N., O’Sullivan G., Rothwell C., Smith G., Burgess S. C., Rennie M., Lee L. F., Davison T. F. 1997; Marek’s disease virus EcoRI-Q gene (meq) and a small RNA antisense to ICP4 are abundantly expressed in CD4+ cells and cells carrying a novel lymphoid marker, AV37, in Marek’s disease lymphomas. J Gen Virol 78:2191–2198[PubMed]
    [Google Scholar]
  39. Schat K. A., Purchase H. G. 1998; Cell-culture methods. In A laboratory Manual for the Isolation and Identification of Avian Pathogens . , 4th edn. pp. 223–234 Kennet Square, PA: American Association of Avian Pathologists;
  40. Shkreli M., Dambrine G., Soubieux D., Kut E., Rasschaert D. 2007; Involvement of the oncoprotein c-Myc in viral telomerase RNA gene regulation during Marek’s disease virus-induced lymphomagenesis. J Virol 81:4848–4857 [CrossRef][PubMed]
    [Google Scholar]
  41. Tahiri-Alaoui A., Matsuda D., Xu H., Panagiotis P., Burman L., Lambeth L. S., Petherbridge L., James W., Mauro V., Nair V. 2009; The 5′ leader of the mRNA encoding the Marek’s disease virus serotype 1 pp14 protein contains an intronic internal ribosome entry site with allosteric properties. J Virol 83:12769–12778 [CrossRef][PubMed]
    [Google Scholar]
  42. Trapp S., Parcells M. S., Kamil J. P., Schumacher D., Tischer B. K., Kumar P. M., Nair V. K., Osterrieder N. 2006; A virus-encoded telomerase RNA promotes malignant T cell lymphomagenesis. J Exp Med 203:1307–1317 [CrossRef][PubMed]
    [Google Scholar]
  43. Tulman E. R., Afonso C. L., Lu Z., Zsak L., Rock D. L., Kutish G. F. 2000; The genome of a very virulent Marek’s disease virus. J Virol 74:7980–7988 [CrossRef][PubMed]
    [Google Scholar]
  44. Yao Y., Zhao Y., Xu H., Smith L. P., Lawrie C. H., Watson M., Nair V. 2008; MicroRNA profile of Marek’s disease virus-transformed T-cell line MSB-1: predominance of virus-encoded microRNAs. J Virol 82:4007–4015 [CrossRef][PubMed]
    [Google Scholar]
  45. Zhao Y., Xu H., Yao Y., Smith L. P., Kgosana L., Green J., Petherbridge L., Baigent S. J., Nair V. 2011; Critical role of the virus-encoded microRNA-155 ortholog in the induction of Marek’s disease lymphomas. PLoS Pathog 7:e1001305 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.040741-0
Loading
/content/journal/jgv/10.1099/vir.0.040741-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error