1887

Journal of General Virology header logo

Volume 97, Issue 11

BRD4 is associated with raccoon polyomavirus genome and mediates viral gene transcription and maintenance of a stem cell state in neuroglial tumour cells Free

Abstract

Polyomavirus infection often results in persistence of the viral genome with little or no virion production. However, infection of certain cell types can result in high viral gene transcription and either cytolysis or neoplastic transformation. While infection by polyomavirus is common in humans and many animals, major questions regarding viral persistence of most polyomaviruses remain unanswered. Specifically, identification of target cells for viral infection and the mechanisms polyomaviruses employ to maintain viral genomes within cells are important not only in ascribing causality to polyomaviruses in disease, but in understanding specific mechanisms by which they cause disease. Here, we characterize the cell of origin in raccoon polyomavirus (RacPyV)-associated neuroglial brain tumours as a neural stem cell. Moreover, we identify an association between the viral genome and the host cell bromodomain protein, BRD4, which is involved in numerous cellular functions, including cell cycle progression, differentiation of stem cells, tethering of persistent DNA viruses, and regulation of viral and host-cell gene transcription. We demonstrate that inhibition of BRD4 by the small molecule inhibitors (+)-JQ1 and IBET-151 (GSK1210151A) results in reduced RacPyV genome within cells as well as significant reduction of viral gene transcripts LT and VP1, highlighting its importance in both maintenance of the viral genome and in driving oncogenic transformation by RacPyV. This work implicates BRD4 as a central protein involved in RacPyV neuroglial tumour cell proliferation and in the maintenance of a stem cell state.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): BRD4 , Neural Stem Cell , polyomavirus , Raccoon and Viral Oncogenesis
© Microbiology Society
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.000594
2016-11-10
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/97/11/2939.html?itemId=/content/journal/jgv/10.1099/jgv.0.000594&mimeType=html&fmt=ahah

References

  1. Ahmed S. 2009; The culture of neural stem cells. J Cell Biochem 106:1–6 [View Article][PubMed]
     [Google Scholar]
  2. Bialasiewicz S., Whiley D. M., Lambert S. B., Nissen M. D., Sloots T. P. 2009; Detection of BK, JC, WU, or KI polyomaviruses in faecal, urine, blood, cerebrospinal fluid and respiratory samples. J Clin Virol 45:249–254 [View Article][PubMed]
     [Google Scholar]
  3. Brostoff T., Dela Cruz F. N., Church M. E., Woolard K. D., Pesavento P. A. 2014; The raccoon polyomavirus genome and tumor antigen transcription are stable and abundant in neuroglial tumors. J Virol 88:12816–12824 [View Article][PubMed]
     [Google Scholar]
  4. Chesters P. M., Heritage J., McCance D. J. 1983; Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis 147:676–684 [View Article][PubMed]
     [Google Scholar]
  5. Church M. E., Dela Cruz F. N., Estrada M., Leutenegger C. M., Pesavento P. A., Woolard K. D. 2016; Exposure to raccoon polyomavirus (RacPyV) in free-ranging North American raccoons (Procyon lotor). Virology 489:292–299 [View Article][PubMed]
     [Google Scholar]
  6. DeCaprio J. A., Garcea R. L. 2013; A cornucopia of human polyomaviruses. Nat Rev Microbiol 11:264–276 [View Article][PubMed]
     [Google Scholar]
  7. Dela Cruz F. N., Giannitti F., Li L., Woods L. W., Del Valle L., Delwart E., Pesavento P. A. 2013; Novel polyomavirus associated with brain tumors in free-ranging raccoons, western United States. Emerg Infect Dis 19:77–84 [View Article][PubMed]
     [Google Scholar]
  8. Di Micco R., Fontanals-Cirera B., Low V., Ntziachristos P., Yuen S. K., Lovell C. D., Dolgalev I., Yonekubo Y., Zhang G. et al. 2014; Control of embryonic stem cell identity by BRD4-dependent transcriptional elongation of super-enhancer-associated pluripotency genes. Cell Rep 9:234–247 [View Article][PubMed]
     [Google Scholar]
  9. Dubensky T. W., Villarreal L. P. 1984; The primary site of replication alters the eventual site of persistent infection by polyomavirus in mice. J Virol 50:541–546[PubMed]
     [Google Scholar]
  10. Feng H., Shuda M., Chang Y., Moore P. S. 2008; Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319:1096–1100 [View Article][PubMed]
     [Google Scholar]
  11. Ferenczy M. W., Johnson K. R., Marshall L. J., Monaco M. C., Major E. O. 2013; Differentiation of human fetal multipotential neural progenitor cells to astrocytes reveals susceptibility factors for JC virus. J Virol 87:6221–6231 [View Article][PubMed]
     [Google Scholar]
  12. Gage F. H. 2000; Mammalian neural stem cells. Science 287:1433–1438 [View Article][PubMed]
     [Google Scholar]
  13. Giannitti F., Higgins R. J., Pesavento P. A., Dela Cruz F., Clifford D. L., Piazza M., Parker Struckhoff A., Del Valle L., Bollen A. W. et al. 2014; Temporal and geographic clustering of polyomavirus-associated olfactory tumors in 10 free-ranging raccoons (Procyon lotor). Vet Pathol 51:832–845 [View Article][PubMed]
     [Google Scholar]
  14. Gosert R., Kardas P., Major E. O., Hirsch H. H. 2010; Rearranged JC virus noncoding control regions found in progressive multifocal leukoencephalopathy patient samples increase virus early gene expression and replication rate. J Virol 84:10448–10456 [View Article][PubMed]
     [Google Scholar]
  15. Horne G. A., Stewart H. J., Dickson J., Knapp S., Ramsahoye B., Chevassut T. 2015; Nanog requires BRD4 to maintain murine embryonic stem cell pluripotency and is suppressed by bromodomain inhibitor JQ1 together with Lefty1. Stem Cells Dev 24:879–891 [View Article][PubMed]
     [Google Scholar]
  16. Josling G. A., Selvarajah S. A., Petter M., Duffy M. F. 2012; The role of bromodomain proteins in regulating gene expression. Genes 3:320–343 [View Article][PubMed]
     [Google Scholar]
  17. Lemasson G., Coquart N., Lebonvallet N., Boulais N., Galibert M. D., Marcorelles P., Misery L. 2012; Presence of putative stem cells in Merkel cell carcinomas. J Eur Acad Dermatol Venereol 26:789–795 [View Article][PubMed]
     [Google Scholar]
  18. Lin A., Wang S., Nguyen T., Shire K., Frappier L. 2008; The EBNA1 protein of Epstein-Barr virus functionally interacts with Brd4. J Virol 82:12009–12019 [View Article][PubMed]
     [Google Scholar]
  19. Liu W., Stein P., Cheng X., Yang W., Shao N. Y., Morrisey E. E., Schultz R. M., You J. 2014; BRD4 regulates Nanog expression in mouse embryonic stem cells and preimplantation embryos. Cell Death Differ 21:1950–1960 [View Article][PubMed]
     [Google Scholar]
  20. Mapes S., Leutenegger C. M., Pusterla N. 2008; Nucleic acid extraction methods for detection of EHV-1 from blood and nasopharyngeal secretions. Vet Rec 162:857–859 [View Article][PubMed]
     [Google Scholar]
  21. McBride A. A., Sakakibara N., Stepp W. H., Jang M. K. 2012; Hitchhiking on host chromatin: how papillomaviruses persist. Biochim Biophys Acta 1819:820–825 [View Article][PubMed]
     [Google Scholar]
  22. McBride A. A., Jang M. K. 2013; Current understanding of the role of the Brd4 protein in the papillomavirus lifecycle. Viruses 5:1374–1394 [View Article][PubMed]
     [Google Scholar]
  23. Mochizuki K., Nishiyama A., Jang M. K., Dey A., Ghosh A., Tamura T., Natsume H., Yao H., Ozato K. 2008; The bromodomain protein Brd4 stimulates G1 gene transcription and promotes progression to S phase. J Biol Chem 283:9040–9048 [View Article][PubMed]
     [Google Scholar]
  24. Moore P. S., Chang Y. 2010; Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer 10:878–889 [View Article][PubMed]
     [Google Scholar]
  25. Ottinger M., Christalla T., Nathan K., Brinkmann M. M., Viejo-Borbolla A., Schulz T. F. 2006; Kaposi's sarcoma-associated herpesvirus LANA-1 interacts with the short variant of BRD4 and releases cells from a BRD4- and BRD2/RING3-induced G1 cell cycle arrest. J Virol 80:10772–10786 [View Article][PubMed]
     [Google Scholar]
  26. Reynolds B. A., Weiss S. 1992; Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255:1707–1710 [View Article][PubMed]
     [Google Scholar]
  27. Rodriguez R. M., Suarez-Alvarez B., Salvanés R., Huidobro C., Toraño E. G., Garcia-Perez J. L., Lopez-Larrea C., Fernandez A. F., Bueno C. et al. 2014; Role of BRD4 in hematopoietic differentiation of embryonic stem cells. Epigenetics 9:566–578 [View Article][PubMed]
     [Google Scholar]
  28. Sadeghi M., Aaltonen L. M., Hedman L., Chen T., Söderlund-Venermo M., Hedman K. 2014; Detection of TS polyomavirus DNA in tonsillar tissues of children and adults: evidence for site of viral latency. J Clin Virol 59:55–58 [View Article][PubMed]
     [Google Scholar]
  29. Sanai N., Alvarez-Buylla A., Berger M. S. 2005; Mechanisms of disease: neural stem cells and the origin of gliomas. N Engl J Med 353:811–822 [CrossRef]
     [Google Scholar]
  30. Sun W., Kim H., Moon Y. 2010; Control of neuronal migration through rostral migration stream in mice. Anat Cell Biol 43:269–279 [View Article][PubMed]
     [Google Scholar]
  31. Swanson P. A., Lukacher A. E., Szomolanyi-Tsuda E. 2009; Immunity to polyomavirus infection: the polyomavirus–mouse model. Semin Cancer Biol 19:244–251 [View Article][PubMed]
     [Google Scholar]
  32. Tilling T., Moll I. 2012; Which are the cells of origin in Merkel cell carcinoma?. J Skin Cancer 2012:680410 [View Article][PubMed]
     [Google Scholar]
  33. Wang X., Li J., Schowalter R. M., Jiao J., Buck C. B., You J. 2012; Bromodomain protein Brd4 plays a key role in Merkel cell polyomavirus DNA replication. PLoS Pathog 8:e1003021 [View Article][PubMed]
     [Google Scholar]
  34. White M. K., Gordon J., Khalili K. 2013; The rapidly expanding family of human polyomaviruses: recent developments in understanding their life cycle and role in human pathology. PLoS Pathog 9:e1003206 [View Article][PubMed]
     [Google Scholar]
  35. Wirth J. J., Martin L. G., Fluck M. M. 1997; Oncogenesis of mammary glands, skin, and bones by polyomavirus correlates with viral persistence and prolonged genome replication potential. J Virol 71:1072–1078[PubMed]
     [Google Scholar]
  36. Wollebo H. S., Bellizzi A., Cossari D. H., Salkind J., Safak M., White M. K. 2016; The Brd4 acetyllysine-binding protein is involved in activation of polyomavirus JC. J Neurovirol 22:615–625 [View Article][PubMed]
     [Google Scholar]
  37. Wu T., Pinto H. B., Kamikawa Y. F., Donohoe M. E. 2015; The BET family member BRD4 interacts with OCT4 and regulates pluripotency gene expression. Stem Cell Reports 4:390–403 [View Article][PubMed]
     [Google Scholar]
  38. You J., Croyle J. L., Nishimura A., Ozato K., Howley P. M. 2004; Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell 117:349–360 [View Article][PubMed]
     [Google Scholar]
  39. You J., Srinivasan V., Denis G. V., Harrington W. J., Ballestas M. E., Kaye K. M., Howley P. M. 2006; Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J Virol 80:8909–8919 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.000594
Loading
BRD4 is associated with raccoon polyomavirus genome and mediates viral gene transcription and maintenance of a stem cell state in neuroglial tumour cells
J. Gen. Virol. 97, 2939 (2016); https://doi.org/10.1099/jgv.0.000594
/content/journal/jgv/10.1099/jgv.0.000594
/content/journal/jgv/10.1099/jgv.0.000594
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF

Most cited 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