Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Keeping it quiet: chromatin control of gammaherpesvirus latency

Key Points

  • Gammaherpesvirus latency is a programmed event with multiple epigenetic steps.

  • During latency, the viral genome establishes a metastable epigenetic pattern of histone modifications and DNA methylation.

  • Epigenetic patterns and chromosome conformations are stabilized by host chromatin boundary factors, such as CCCTC-binding factor (CTCF) and cohesin.

  • Lytic reactivation is a stochastic process that is controlled by multiple epigenetic barriers.

Abstract

The human gammaherpesviruses Epstein–Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) establish long-term latent infections associated with diverse human cancers. Viral oncogenesis depends on the ability of the latent viral genome to persist in host nuclei as episomes that express a restricted yet dynamic pattern of viral genes. Multiple epigenetic events control viral episome generation and maintenance. This Review highlights some of the recent findings on the role of chromatin assembly, histone and DNA modifications, and higher-order chromosome structures that enable gammaherpesviruses to establish stable latent infections that mediate viral pathogenesis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Early events that regulate the establishment of a latent gammaherpesvirus minichromosome.
Figure 2: Establishment of the EBV epigenome.
Figure 3: Establishment of the KSHV epigenome.
Figure 4: Episome maintenance and viral chromosome structure.
Figure 5: Chromosome control of lytic reactivation.

Similar content being viewed by others

References

  1. Young, L. S. & Rickinson, A. B. Epstein–Barr virus: 40 years on. Nature Rev. Cancer 4, 757–768 (2004).

    Article  CAS  Google Scholar 

  2. Wen, K. W. & Damania, B. Kaposi sarcoma-associated herpesvirus (KSHV): molecular biology and oncogenesis. Cancer Lett. 289, 140–150 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Thorley-Lawson, D. A., Hawkins, J. B., Tracy, S. I. & Shapiro, M. The pathogenesis of Epstein–Barr virus persistent infection. Curr. Opin. Virol. 3, 227–232 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mesri, E. A., Cesarman, E. & Boshoff, C. Kaposi's sarcoma and its associated herpesvirus. Nature Rev. Cancer 10, 707–719 (2010).

    Article  CAS  Google Scholar 

  5. Turner, B. M. Epigenetic responses to environmental change and their evolutionary implications. Phil. Trans. R. Soc. B. Biol. Sci. 364, 3403–3418 (2009).

    Article  CAS  Google Scholar 

  6. Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy. Cell 150, 12–27 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Deng, Z., Wang, Z. & Lieberman, P. M. Telomeres and viruses: common themes of genome maintenance. Frontiers Oncol. 2, 201 (2012).

    Article  Google Scholar 

  8. Placek, B. J. et al. The histone variant H3.3 regulates gene expression during lytic infection with herpes simplex virus type 1. J. Virol. 83, 1416–1421 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Ballestas, M. E., Chatis, P. A. & Kaye, K. M. Efficient persistence of extrachromosomal KSHV DNA mediated by latency-associated nuclear antigen. Science 284, 641–644 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Strang, B. L. & Stow, N. D. Circularization of the herpes simplex virus type 1 genome upon lytic infection. J. Virol. 79, 12487–12494 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kalla, M. & Hammerschmidt, W. Human B cells on their route to latent infection-early but transient expression of lytic genes of Epstein–Barr virus. Eur. J. Cell Biol. 91, 65–69 (2011).

    Article  PubMed  CAS  Google Scholar 

  12. Hurley, E. A. et al. When Epstein–Barr virus persistently infects B-cell lines, it frequently integrates. J. Virol. 65, 1245–1254 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zimmermann, J. & Hammerschmidt, W. Structure and role of the terminal repeats of Epstein–Barr virus in processing and packaging of virion DNA. J. Virol. 69, 3147–3155 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kintner, C. R. & Sugden, B. The structure of the termini of the DNA of Epstein–Barr virus. Cell 17, 661–671 (1979).

    Article  CAS  PubMed  Google Scholar 

  15. Delecluse, H. J., Kohls, S., Bullerdiek, J. & Bornkamm, G. W. Integration of EBV in Burkitt's lymphoma cells. Curr. Top. Microbiol. Immunol. 182, 367–373 (1992).

    CAS  PubMed  Google Scholar 

  16. Weitzman, M. D., Lilley, C. E. & Chaurushiya, M. S. Genomes in conflict: maintaining genome integrity during virus infection. Annu. Rev. Microbiol. 64, 61–81 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Smeenk, G. & van Attikum, H. The chromatin response to DNA breaks: leaving a mark on genome integrity. Annu. Rev. Biochem. 82, 55–80 (2013).

    Article  CAS  PubMed  Google Scholar 

  18. Nikitin, P. A. et al. An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein–Barr virus transformation of primary human B cells. Cell Host Microbe 8, 510–522 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shiloh, Y. ATM and related protein kinases: safeguarding genome integrity. Nature Rev. Cancer 3, 155–168 (2003).

    CAS  Google Scholar 

  20. Kulinski, J. M. et al. Ataxia telangiectasia mutated kinase controls chronic gammaherpesvirus infection. J. Virol. 86, 12826–12837 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mounce, B. C. et al. Gammaherpesvirus gene expression and DNA synthesis are facilitated by viral protein kinase and histone variant H2AX. Virology 420, 73–81 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Mounce, B. C., Tsan, F. C., Kohler, S., Cirillo, L. A. & Tarakanova, V. L. Dynamic association of gammaherpesvirus DNA with core histone during de novo lytic infection of primary cells. Virology 421, 167–172 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Jha, H. C. et al. H2AX phosphorylation is important for LANA mediated KSHV episome persistence. J. Virol. 87, 5255–5269 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zentner, G. E. & Henikoff, S. Regulation of nucleosome dynamics by histone modifications. Nature Struct. Mol. Biol. 20, 259–266 (2013).

    Article  CAS  Google Scholar 

  25. Hurley, E. A. & Thorley-Lawson, D. A. B cell activation and the establishment of Epstein–Barr virus latency. J. Exp. Med. 168, 2059–2075 (1988).

    Article  CAS  PubMed  Google Scholar 

  26. Darst, R. P., Haecker, I., Pardo, C. E., Renne, R. & Kladde, M. P. Epigenetic diversity of Kaposi's sarcoma-associated herpesvirus. Nucleic Acids Res. 41, 2993–3009 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Peng, H., Nogueira, M. L., Vogel, J. L. & Kristie, T. M. Transcriptional coactivator HCF-1 couples the histone chaperone Asf1b to HSV-1 DNA replication components. Proc. Natl Acad. Sci. USA 107, 2461–2466 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Oh, J., Ruskoski, N. & Fraser, N. W. Chromatin assembly on herpes simplex virus 1 DNA early during a lytic infection is Asf1a dependent. J. Virol. 86, 12313–12321 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Maul, G. G., Negorev, D., Bell, P. & Ishov, A. M. Review: properties and assembly mechanisms of ND10, PML bodies, or PODs. J. Struct. Biol. 129, 278–287 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Lindsay, C. R., Morozov, V. M. & Ishov, A. M. PML NBs (ND10) and Daxx: from nuclear structure to protein function. Frontiers Biosci. 13, 7132–7142 (2008).

    Article  CAS  Google Scholar 

  31. Tavalai, N. & Stamminger, T. Interplay between herpesvirus infection and host defense by PML nuclear bodies. Viruses 1, 1240–1264 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lewis, P. W., Elsaesser, S. J., Noh, K. M., Stadler, S. C. & Allis, C. D. Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc. Natl Acad. Sci. USA 107, 14075–14080 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Goldberg, A. D. et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678–691 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Drane, P., Ouararhni, K., Depaux, A., Shuaib, M. & Hamiche, A. The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 24, 1253–1265 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tang, Q. & Maul, G. G. Mouse cytomegalovirus immediate-early protein 1 binds with host cell repressors to relieve suppressive effects on viral transcription and replication during lytic infection. J. Virol. 77, 1357–1367 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Greger, J. G., Katz, R. A., Ishov, A. M., Maul, G. G. & Skalka, A. M. The cellular protein Daxx interacts with avian sarcoma virus integrase and viral DNA to repress viral transcription. J. Virol. 79, 4610–4618 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ling, P. D. et al. Mediation of Epstein–Barr virus EBNA-LP transcriptional coactivation by Sp100. EMBO J. 24, 3565–3575 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Negorev, D. G. et al. Differential role of Sp100 isoforms in interferon-mediated repression of herpes simplex virus type 1 immediate-early protein expression. J. Virol. 80, 8019–8029 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tsai, K., Thikmyanova, N., Wojcechowskyj, J. A., Delecluse, H. J. & Lieberman, P. M. EBV tegument protein BNRF1 disrupts DAXX–ATRX to activate viral early gene transcription. PLoS Pathog. 7, e1002376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ling, P. D., Tan, J., Sewatanon, J. & Peng, R. Murine gammaherpesvirus 68 open reading frame 75c tegument protein induces the degradation of PML and is essential for production of infectious virus. J. Virol. 82, 8000–8012 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Everett, R. D. & Chelbi-Alix, M. K. PML and PML nuclear bodies: implications in antiviral defence. Biochimie 89, 819–830 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Rowe, M. et al. Differences in B-cell growth phenotype reflect novel patterns of Epstein–Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 6, 2743–2751 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Babcock, G. J., Hochberg, D. & Thorley-Lawson, A. D. The expression pattern of Epstein–Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13, 497–506 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Zimber-Strobl, U. & Strobl, L. J. EBNA2 and Notch signalling in Epstein–Barr virus mediated immortalization of B lymphocytes. Seminars Cancer Biol. 11, 423–434 (2001).

    Article  CAS  Google Scholar 

  45. Sjoblom, A. et al. PU box-binding transcription factors and a POU domain protein cooperate in the Epstein–Barr virus (EBV) nuclear antigen 2-induced transactivation of the EBV latent membrane protein 1 promoter. J. Gen. Virol. 76, 2679–2692 (1995).

    Article  PubMed  Google Scholar 

  46. Laux, G., Adam, B., Strobl, L. J. & Moreau-Gachelin, F. The Spi-1/PU.1 and Spi-B ets family transcription factors and the recombination signal binding protein RBP-Jκ interact with an Epstein–Barr virus nuclear antigen 2 responsive cis-element. EMBO J. 13, 5624–5632 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tierney, R., Kirby, H., Nagra, J., Rickinson, A. & Bell, A. The Epstein–Barr virus promoter initiating B-cell transformation is activated by RFX proteins and the B-cell-specific activator protein BSAP/Pax5. J. Virol. 74, 10458–10467 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Tierney, R. et al. Epstein–Barr virus exploits BSAP/Pax5 to achieve the B-cell specificity of its growth-transforming program. J. Virol. 81, 10092–10100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Borestrom, C., Forsman, A., Ruetschi, U. & Rymo, L. E2F1, ARID3A/Bright and Oct-2 factors bind to the Epstein–Barr virus C promoter, EBNA1 and oriP, participating in long-distance promoter-enhancer interactions. J. Gen. Virol. 93, 1065–1075 (2012).

    Article  PubMed  CAS  Google Scholar 

  50. Altmann, M. et al. Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV's transforming genes. Proc. Natl Acad. Sci. USA 103, 14188–14193 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tsai, C. N., Liu, S. T. & Chang, Y. S. Identification of a novel promoter located within the Bam, HIQ region of the Epstein–Barr virus genome for the EBNA 1 gene. DNA Cell Biol. 14, 767–776 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. Schlager, S., Speck, S. H. & Woisetschlager, M. Transcription of the Epstein–Barr virus nuclear antigen 1 (EBNA1) gene occurs before induction of the BCR2 (Cp) EBNA gene promoter during the initial stages of infection in B cells. J. Virol. 70, 3561–3570 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nonkwelo, C., Ruf, I. K. & Sample, J. The Epstein–Barr virus EBNA-1 promoter Qp requires an initiator-like element. J. Virol. 71, 354–361 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ambinder, R. F., Robertson, K. D. & Tao, Q. DNA methylation and the Epstein–Barr virus. Seminars Cancer Biol. 9, 369–375 (1999).

    Article  CAS  Google Scholar 

  55. Minarovits, J. Epigenotypes of latent herpesvirus genomes. Curr. Top. Microbiol. Immunol. 310, 61–80 (2006).

    CAS  PubMed  Google Scholar 

  56. Woellmer, A. & Hammerschmidt, W. Epstein–Barr virus and host cell methylation: regulation of latency, replication and virus reactivation. Curr. Opin. Virol. 3, 260–265 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Arvey, A. et al. An atlas of the Epstein–Barr virus transcriptome and epigenome reveals host–virus regulatory interactions. Cell Host Microbe 12, 233–245 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kraus, R. J., Perrigoue, J. G. & Mertz, J. E. ZEB negatively regulates the lytic-switch BZLF1 gene promoter of Epstein–Barr virus. J. Virol. 77, 199–207 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hagemeier, S. R. et al. Sumoylation of the Epstein–Barr virus BZLF1 protein inhibits its transcriptional activity and is regulated by the virus-encoded protein kinase. J. Virol. 84, 4383–4394 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Robinson, A. R., Kwek, S. S. & Kenney, S. C. The B-cell specific transcription factor, Oct-2, promotes Epstein–Barr virus latency by inhibiting the viral immediate-early protein, BZLF1. PLoS Pathog. 8, e1002516 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Raver, R. M., Panfil, A. R., Hagemeier, S. R. & Kenney, S. C. The B-cell specific transcription factor and master regulator, Pax5, promotes EBV latency by negatively regulating the viral immediate early protein, BZLF1. J. Virol. 87, 8053–8063 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chang, H. H. & Ganem, D. A. Unique herpesviral transcriptional program in KSHV-infected lymphatic endothelial cells leads to mTORC1 activation and rapamycin sensitivity. Cell Host Microbe 13, 429–440 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ballestas, M. E. & Kaye, K. M. The latency-associated nuclear antigen, a multifunctional protein central to Kaposi's sarcoma-associated herpesvirus latency. Future Microbiol. 6, 1399–1413 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Verma, S. C., Lan, K. & Robertson, E. Structure and function of latency-associated nuclear antigen. Curr. Top. Microbiol. Immunol. 312, 101–136 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Leidal, A. M., Pringle, E. S. & McCormick, C. Evasion of oncogene-induced senescence by gammaherpesviruses. Curr. Opin. Virol. 2, 748–754 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Jeong, J., Papin, J. & Dittmer, D. Differential regulation of the overlapping Kaposi's sarcoma-associated herpesvirus vGCR (orf74) and LANA (orf73) promoters. J. Virol. 75, 1798–1807 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jeong, J. H. et al. Regulation and autoregulation of the promoter for the latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus. J. Biol. Chem. 279, 16822–16831 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Li, H., Komatsu, T., Dezube, B. J. & Kaye, K. M. The Kaposi's sarcoma-associated herpesvirus K12 transcript from a primary effusion lymphoma contains complex repeat elements, is spliced, and initiates from a novel promoter. J. Virol. 76, 11880–11888 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Pearce, M., Matsumura, S. & Wilson, A. C. Transcripts encoding K12, v-FLIP, v-cyclin, and the microRNA cluster of Kaposi's sarcoma-associated herpesvirus originate from a common promoter. J. Virol. 79, 14457–14464 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fakhari, F. D. & Dittmer, D. P. Charting latency transcripts in Kaposi's sarcoma-associated herpesvirus by whole-genome real-time quantitative PCR. J. Virol. 76, 6213–6223 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Dittmer, D. P. Transcription profile of Kaposi's sarcoma-associated herpesvirus in primary Kaposi's sarcoma lesions as determined by real-time PCR arrays. Cancer Res. 63, 2010–2015 (2003).

    CAS  PubMed  Google Scholar 

  72. Nador, R. G. et al. Expression of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor monocistronic and bicistronic transcripts in primary effusion lymphomas. Virology 287, 62–70 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Hayward, G. S. Initiation of angiogenic Kaposi's sarcoma lesions. Cancer Cell 3, 1–3 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Montaner, S. et al. Endothelial infection with KSHV genes in vivo reveals that vGPCR initiates Kaposi's sarcomagenesis and can promote the tumorigenic potential of viral latent genes. Cancer Cell 3, 23–36 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Sodhi, A., Montaner, S. & Gutkind, J. S. Does dysregulated expression of a deregulated viral GPCR trigger Kaposi's sarcomagenesis? FASEB J. 18, 422–427 (2004).

    Article  CAS  PubMed  Google Scholar 

  76. Mutlu, A. D. et al. In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma. Cancer Cell 11, 245–258 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Toth, Z., Brulois, K. & Jung, J. U. The chromatin landscape of Kaposi's sarcoma-associated herpesvirus. Viruses 5, 1346–1373 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Murata, T. & Tsurumi, T. Epigenetic modification of the Epstein–Barr virus BZLF1 promoter regulates viral reactivation from latency. Frontiers Genet. 4, 53 (2013).

    Article  CAS  Google Scholar 

  79. Klein, G., Klein, E. & Kashuba, E. Interaction of Epstein–Barr virus (EBV) with human B-lymphocytes. Biochem. Biophys. Res. Commun. 396, 67–73 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Takacs, M. et al. Epigenetic regulation of latent Epstein–Barr virus promoters. Biochim. Biophys. Acta 1799, 228–235 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Gunther, T. & Grundhoff, A. The epigenetic landscape of latent Kaposi sarcoma-associated herpesvirus genomes. PLoS Pathog. 6, e1000935 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Karlsson, Q. H., Schelcher, C., Verrall, E., Petosa, C. & Sinclair, A. J. The reversal of epigenetic silencing of the EBV genome is regulated by viral bZIP protein. Biochem. Soc. Trans. 36, 637–639 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Karlsson, Q. H., Schelcher, C., Verrall, E., Petosa, C. & Sinclair, A. J. Methylated DNA recognition during the reversal of epigenetic silencing is regulated by cysteine and serine residues in the Epstein–Barr virus lytic switch protein. PLoS Pathog. 4, e1000005 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Ramasubramanyan, S., Osborn, K., Flower, K. & Sinclair, A. J. Dynamic chromatin environment of key lytic cycle regulatory regions of the Epstein–Barr virus genome. J. Virol. 86, 1809–1819 (2011).

    Article  PubMed  CAS  Google Scholar 

  85. Ramasubramanyan, S. et al. Genome-wide analyses of Zta binding to the Epstein–Barr virus genome reveals interactions in both early and late lytic cycles and an epigenetic switch leading to an altered binding profile. J. Virol. 86, 12494–12502 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bhende, P. M., Seaman, W. T., Delecluse, H. J. & Kenney, S. C. The EBV lytic switch protein, Z, preferentially binds to and activates the methylated viral genome. Nature Genet. 36, 1099–1104 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Bhende, P. M., Seaman, W. T., Delecluse, H. J. & Kenney, S. C. BZLF1 activation of the methylated form of the BRLF1 immediate-early promoter is regulated by BZLF1 residue 186. J. Virol. 79, 7338–7348 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Bergbauer, M. et al. CpG-methylation regulates a class of Epstein–Barr virus promoters. PLoS Pathog. 6, e1001114 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Kalla, M., Gobel, C. & Hammerschmidt, W. The lytic phase of Epstein–Barr virus requires a viral genome with 5-methylcytosine residues in CpG sites. J. Virol. 86, 447–458 (2011).

    Article  PubMed  CAS  Google Scholar 

  90. Fejer, G. et al. Latency type-specific distribution of epigenetic marks at the alternative promoters Cp and Qp of Epstein–Barr virus. J. General Virol. 89, 1364–1370 (2008).

    Article  CAS  Google Scholar 

  91. Miller, G. et al. Antibodies to butyrate-inducible antigens of Kaposi's sarcoma-associated herpesvirus in patients with HIV-1 infection. New Engl. J. Med. 334, 1292–1297 (1996).

    Article  CAS  PubMed  Google Scholar 

  92. Alazard, N., Gruffat, H., Hiriart, E., Sergeant, A. & Manet, E. Differential hyperacetylation of histones H3 and H4 upon promoter-specific recruitment of EBNA2 in Epstein–Barr virus chromatin. J. Virol. 77, 8166–8172 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lu, F. et al. Chromatin remodeling of the Kaposi's sarcoma-associated herpesvirus ORF50 promoter correlates with reactivation from latency. J. Virol. 77, 11425–11435 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Day, L. et al. Chromatin profiling of Epstein–Barr virus latency control region. J. Virol. 81, 6389–6401 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Arvey, A., Tempera, I. & Lieberman, P. M. Interpreting the Epstein–Barr Virus (EBV) epigenome using high-throughput data. Viruses 5, 1042–1054 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Toth, Z. et al. Epigenetic analysis of KSHV latent and lytic genomes. PLoS Pathog. 6, e1001013 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Holdorf, M. M., Cooper, S. B., Yamamoto, K. R. & Miranda, J. J. Occupancy of chromatin organizers in the Epstein–Barr virus genome. Virology 415, 1–5 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Cao, R. & Zhang, Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr. Opin. Genet. Dev. 14, 155–164 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Van Bortle, K. & Corces, V. G. Spinning the web of cell fate. Cell 152, 1213–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Van Bortle, K. & Corces, V. G. The role of chromatin insulators in nuclear architecture and genome function. Curr. Opin. Genet. Dev. 23, 212–218 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Dorsett, D. Cohesin: genomic insights into controlling gene transcription and development. Curr. Opin. Genet. Dev. 21, 199–206 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Herold, M., Bartkuhn, M. & Renkawitz, R. CTCF: insights into insulator function during development. Development 139, 1045–1057 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Ohlsson, R., Renkawitz, R. & Lobanenkov, V. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 17, 520–527 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Phillips, J. E. & Corces, V. G. CTCF: master weaver of the genome. Cell 137, 1194–1211 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Ohlsson, R., Lobanenkov, V. & Klenova, E. Does CTCF mediate between nuclear organization and gene expression? BioEssays 32, 37–50 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Weth, O. & Renkawitz, R. CTCF function is modulated by neighboring DNA binding factors. Biochem. Cell Biol. 89, 459–468 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. Chien, R., Zeng, W., Ball, A. R. & Yokomori, K. Cohesin: a critical chromatin organizer in mammalian gene regulation. Biochem. Cell Biol. 89, 445–458 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Losada, A. Cohesin regulation: fashionable ways to wear a ring. Chromosoma 116, 321–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Stedman, W. et al. Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators. EMBO J. 27, 654–666 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Kang, H., Cho, H., Sung, G. H. & Lieberman, P. M. CTCF regulates Kaposi's sarcoma-associated herpesvirus latency transcription by nucleosome displacement and RNA polymerase programming. J. Virol. 87, 1789–1799 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Smolle, M. & Workman, J. L. Transcription-associated histone modifications and cryptic transcription. Biochim. Biophys. Acta 1829, 84–97 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Tempera, I., Wiedmer, A., Dheekollu, J. & Lieberman, P. M. CTCF prevents the epigenetic drift of EBV latency promoter Qp. PLoS Pathog. 6 e100148 (2010).

    Article  CAS  Google Scholar 

  114. Chau, C. M. & Lieberman, P. M. Dynamic chromatin boundaries delineate a latency control region of Epstein–Barr virus. J. Virol. 78, 12308–12319 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Salamon, D. et al. Binding of CCCTC-binding factor in vivo to the region located between Rep* and the C promoter of Epstein–Barr virus is unaffected by CpG methylation and does not correlate with Cp activity. J. Gen. Virol. 90, 1183–1189 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Chen, H. S., Wikramasinghe, P., Showe, L. & Lieberman, P. M. Cohesins repress Kaposi's sarcoma-associated herpesvirus immediate early gene transcription during latency. J. Virol. 86, 9454–9464 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tempera, I., Klichinsky, M. & Lieberman, P. M. EBV latency types adopt alternative chromatin conformations. PLoS Pathog. 7, e1002180 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Avolio-Hunter, T. M. & Frappier, L. Mechanistic studies on the DNA linking activity of Epstein–Barr nuclear antigen 1. Nucleic Acids Res. 26, 4462–4470 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Su, W., Middleton, T., Sugden, B. & Echols, H. DNA looping between the origin of replication of Epstein–Barr virus and its enhancer site: stabilization of an origin complex with Epstein–Barr nuclear antigen 1. Proc. Natl Acad. Sci. USA 88, 10870–10874 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Aras, S., Singh, G., Johnston, K., Foster, T. & Aiyar, A. Zinc coordination is required for and regulates transcription activation by Epstein–Barr nuclear antigen 1. PLoS Pathog. 5, e1000469 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Hopfner, K. P. et al. The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. Nature 418, 562–566 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Kang, H., Wiedmer, A., Yuan, Y., Robertson, E. & Lieberman, P. M. Coordination of KSHV latent and lytic gene control by CTCF-cohesin mediated chromosome conformation. PLoS Pathog. 7, e1002140 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lieberman, P. M., Hu, J. & Renne, R. in Human Herpesviruses: Biology, Therapy, and Immunoprophylaxisch. 24 (eds Arvin, A. et al.) (Cambridge University Press, 2007).

    Google Scholar 

  124. Kapoor, P., Lavoie, B. D. & Frappier, L. EBP2 plays a key role in Epstein–Barr virus mitotic segregation and is regulated by aurora family kinases. Mol. Cell. Biol. 25, 4934–4945 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Nayyar, V. K., Shire, K. & Frappier, L. Mitotic chromosome interactions of Epstein–Barr nuclear antigen 1 (EBNA1) and human EBNA1-binding protein 2 (EBP2). J. Cell Sci. 122, 4341–4350 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Shire, K., Ceccarelli, D. F., Avolio-Hunter, T. M. & Frappier, L. EBP2, a human protein that interacts with sequences of the Epstein–Barr virus nuclear antigen 1 important for plasmid maintenance. J. Virol. 73, 2587–2595 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Sears, J. et al. The amino terminus of Epstein–Barr Virus (EBV) nuclear antigen 1 contains AT hooks that facilitate the replication and partitioning of latent EBV genomes by tethering them to cellular chromosomes. J. Virol. 78, 11487–11505 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Norseen, J., Johnson, F. B. & Lieberman, P. M. Role for G-quadruplex RNA binding by Epstein–Barr virus nuclear antigen 1 in DNA replication and metaphase chromosome attachment. J. Virol. 83, 10336–10346 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Barbera, A. J. et al. The nucleosomal surface as a docking station for Kaposi's sarcoma herpesvirus LANA. Science 311, 856–861 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Viejo-Borbolla, A. et al. Brd2/RING3 interacts with a chromatin-binding domain in the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 (LANA-1) that is required for multiple functions of LANA-1. J. Virol. 79, 13618–13629 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. You, J. et al. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes. J. Virol. 80, 8909–8919 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Noguchi, K., Vassilev, A., Ghosh, S., Yates, J. L. & DePamphilis, M. L. The BAH domain facilitates the ability of human Orc1 protein to activate replication origins in vivo. EMBO J. 25, 5372–5382 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Norseen, J. et al. RNA-dependent recruitment of the origin recognition complex. EMBO J. 27, 3024–3035 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Leight, E. R. & Sugden, B. Establishment of an oriP replicon is dependent upon an infrequent, epigenetic event. Mol. Cell. Biol. 21, 4149–4161 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Aggarwal, B. D. & Calvi, B. R. Chromatin regulates origin activity in Drosophila follicle cells. Nature 430, 372–376 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Karnani, N., Taylor, C. M., Malhotra, A. & Dutta, A. Genomic study of replication initiation in human chromosomes reveals the influence of transcription regulation and chromatin structure on origin selection. Mol. Biol. Cell 21, 393–404 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Stedman, W., Deng, Z., Lu, F. & Lieberman, P. M. ORC, MCM, and histone hyperacetylation at the Kaposi's sarcoma-associated herpesvirus latent replication origin. J. Virol. 78, 12566–12575 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Zhou, J. et al. Cell cycle regulation of chromatin at an origin of DNA replication. EMBO J. 24, 1406–1417 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Norio, P. & Schildkraut, C. L. Visualization of DNA replication on individual Epstein–Barr virus episomes. Science 294, 2361–2364 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. Norio, P. & Schildkraut, C. L. Plasticity of DNA replication initiation in Epstein–Barr virus episomes. PLoS Biol. 2, e152 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Norio, P., Schildkraut, C. L. & Yates, J. L. Initiation of DNA replication within oriP is dispensable for stable replication of the latent Epstein–Barr virus chromosome after infection of established cell lines. J. Virol. 74, 8563–8574 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ott, E., Norio, P., Ritzi, M., Schildkraut, C. & Schepers, A. The dyad symmetry element of Epstein–Barr virus is a dominant but dispensable replication origin. PloS One 6, e18609 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Verma, S. C. et al. Single molecule analysis of replicated DNA reveals the usage of multiple KSHV genome regions for latent replication. PLoS Pathog. 7, e1002365 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Nanbo, A., Sugden, A. & Sugden, B. The coupling of synthesis and partitioning of EBV's plasmid replicon is revealed in live cells. EMBO J. 26, 4252–4262 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Dheekollu, J., Chen, H. S., Kaye, K. M. & Lieberman, P. M. Timeless-dependent DNA. replication-coupled recombination promote, KSHV episome maintenance and terminal repeat stability. J. Virol. 87, 3699–3709 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Dheekollu, J. & Lieberman, P. M. The replisome pausing factor Timeless is required for episomal maintenance of latent Epstein–Barr virus. J. Virol. 85, 5853–5863 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Dhar, V. & Schildkraut, C. L. Role of EBNA-1 in arresting replication forks at the Epstein–Barr virus oriP family of tandem repeats. Mol. Cell. Biol. 11, 6268–6278 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Ermakova, O. V., Frappier, L. & Schildkraut, C. L. Role of the EBNA-1 protein in pausing of replication forks in the Epstein–Barr virus genome. J. Biol. Chem. 271, 33009–33017 (1996).

    Article  CAS  PubMed  Google Scholar 

  149. Dheekollu, J., Deng, Z., Wiedmer, A., Weitzman, M. D. & Lieberman, P. M. A role for MRE11, NBS1, and recombination junctions in replication and stable maintenance of EBV episomes. PloS One 2, e1257 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Bastia, D. & Singh, S. K. “Chromosome kissing” and modulation of replication termination. Bioarchitecture 1, 24–28 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Amon, W. & Farrell, P. J. Reactivation of Epstein–Barr virus from latency. Rev. Med. Virol. 15, 149–156 (2005).

    Article  PubMed  Google Scholar 

  152. Guito, J. & Lukac, D. M. KSHV Rta promoter specification and viral reactivation. Frontiers Microbiol. 3, 30 (2012).

    Article  CAS  Google Scholar 

  153. Miller, G., El-Guindy, A., Countryman, J., Ye, J. & Gradoville, L. Lytic cycle switches of oncogenic human gammaherpesviruses. Adv. Cancer Res. 97, 81–109 (2007).

    Article  CAS  PubMed  Google Scholar 

  154. Sinclair, A. J. bZIP proteins of human gammaherpesviruses. J. General Virol. 84, 1941–1949 (2003).

    Article  CAS  Google Scholar 

  155. Sinclair, A. J. Unexpected structure of Epstein–Barr virus lytic cycle activator Zta. Trends Microbiol. 14, 289–291 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Staudt, M. R. & Dittmer, D. P. The Rta/Orf50 transactivator proteins of the gamma-herpesviridae. Curr. Top. Microbiol. Immunol. 312, 71–100 (2007).

    CAS  PubMed  Google Scholar 

  157. Miller, G., El-Guindy, A., Countryman, J., Ye, J. & Gradoville, L. Lytic cycle switches of oncogenic human gammaherpesviruses. Adv. Cancer Res. 97, 81–109 (2007).

    Article  CAS  PubMed  Google Scholar 

  158. Deng, Z. et al. The CBP bromodomain and nucleosome targeting are required for Zta-directed nucleosome acetylation and transcription activation. Mol. Cell. Biol. 23, 2633–2644 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Ellison, T. J., Izumiya, Y., Izumiya, C., Luciw, P. A. & Kung, H. J. A comprehensive analysis of recruitment and transactivation potential of K-Rta and K-bZIP during reactivation of Kaposi's sarcoma-associated herpesvirus. Virology 387, 76–88 (2009).

    Article  CAS  PubMed  Google Scholar 

  160. Yang, Z., Yan, Z. & Wood, C. Kaposi's sarcoma-associated herpesvirus transactivator RTA promotes degradation of the repressors to regulate viral lytic replication. J. Virol. 82, 3590–3603 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Gould, F., Harrison, S. M., Hewitt, E. W. & Whitehouse, A. Kaposi's sarcoma-associated herpesvirus RTA promotes degradation of the Hey1 repressor protein through the ubiquitin proteasome pathway. J. Virol. 83, 6727–6738 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rossetto, C. C. & Pari, G. KSHV PAN RNA associates with demethylases UTX and JMJD3 to activate lytic replication through a physical interaction with the virus genome. PLoS Pathog. 8, e1002680 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Skalska, L., White, R. E., Franz, M., Ruhmann, M. & Allday, M. J. Epigenetic repression of p16INK4A by latent Epstein–Barr virus requires the interaction of EBNA3A and EBNA3C with CtBP. PLoS Pathog. 6, e1000951 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Paschos, K., Parker, G. A., Watanatanasup, E., White, R. E. & Allday, M. J. BIM promoter directly targeted by EBNA3C in Polycomb-mediated repression by EBV. Nucleic Acids Res. 40, 7233–7246 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Lu, F., Day, L., Gao, S. J. & Lieberman, P. M. Acetylation of the latency-associated nuclear antigen regulates repression of Kaposi's sarcoma-associated herpesvirus lytic transcription. J. Virol. 80, 5273–5282 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ye, F. C. et al. Disruption of Kaposi's sarcoma-associated herpesvirus latent nuclear antigen leads to abortive episome persistence. J. Virol. 78, 11121–11129 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sivachandran, N. et al. Contributions of the Epstein–Barr virus EBNA1 protein to gastric carcinoma. J. Virol. 86, 60–68 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Jin, Y. et al. LANA carboxyl terminal amino acids 1052 to 1082 interact with RBP-Jκ and are responsible for LANA-mediated RTA repression. J. Virol. 86, 4956–4969 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Lu, J. et al. The RBP-Jκ binding sites within the RTA promoter regulate KSHV latent infection and cell proliferation. PLoS Pathog. 8, e1002479 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Sivachandran, N., Wang, X. & Frappier, L. Functions of the Epstein–Barr virus EBNA1 protein in viral reactivation and lytic infection. J. Virol. 86, 6146–6158 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Lu, F., Stedman, W., Yousef, M., Renne, R. & Lieberman, P. M. Epigenetic regulation of Kaposi's sarcoma-associated herpesvirus latency by virus-encoded microRNAs that target Rta and the cellular Rbl2–DNMT pathway. J. Virol. 84, 2697–2706 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zhao, M., Zhang, J., Phatnani, H., Scheu, S. & Maniatis, T. Stochastic expression of the interferon-beta gene. PLoS Biol. 10, e1001249 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Daigle, D. et al. Valproic acid antagonizes the capacity of other histone deacetylase inhibitors to activate the Epstein–Barr virus lytic cycle. J. Virol. 85, 5628–5643 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Daigle, D. et al. Upregulation of STAT3 marks Burkitt lymphoma cells refractory to Epstein–Barr virus lytic cycle induction by HDAC inhibitors. J. Virol. 84, 993–1004 (2010).

    Article  CAS  PubMed  Google Scholar 

  175. Davies, M. L. et al. Cellular factors associated with latency and spontaneous Epstein–Barr virus reactivation in B-lymphoblastoid cell lines. Virology 400, 53–67 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Yu, X., Wang, Z. & Mertz, J. E. ZEB1 regulates the latent-lytic switch in infection by Epstein–Barr virus. PLoS Pathog. 3, e194 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  177. Ellis, A. L., Wang, Z., Yu, X. & Mertz, J. E. Either ZEB1 or ZEB2/SIP1 can play a central role in regulating the Epstein–Barr virus latent-lytic switch in a cell-type-specific manner. J. Virol. 84, 6139–6152 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Murata, T. et al. Involvement of Jun dimerization protein 2 (JDP2) in the maintenance of Epstein–Barr virus latency. J. Biol. Chem. 286, 22007–22016 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Wille, C. K. et al. Viral genome methylation differentially affects the ability of BZLF1 versus BRLF1 to activate Epstein–Barr virus lytic gene expression and viral replication. J. Virol. 87, 935–950 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Moore, P. S. & Chang, Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nature Rev. Cancer 10, 878–889 (2010).

    Article  CAS  Google Scholar 

  181. D'Addario, M., Libermann, T. A., Xu, J., Ahmad, A. & Menezes, J. Epstein–Barr virus and its glycoprotein-350 upregulate IL-6 in human B-lymphocytes via CD21, involving activation of NF-κB and different signaling pathways. J. Mol. Biol. 308, 501–514 (2001).

    Article  CAS  PubMed  Google Scholar 

  182. Chakraborty, S., Veettil, M. V., Bottero, V. & Chandran, B. Kaposi's sarcoma-associated herpesvirus interacts with EphrinA2 receptor to amplify signaling essential for productive infection. Proc. Natl Acad. Sci. USA 109, E1163–E1172 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hahn, A. S. et al. The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma-associated herpesvirus. Nature Med. 18, 961–966 (2012).

    Article  CAS  PubMed  Google Scholar 

  184. Chandran, B. Early events in Kaposi's sarcoma-associated herpesvirus infection of target cells. J. Virol. 84, 2188–2199 (2010).

    Article  CAS  PubMed  Google Scholar 

  185. Liashkovich, I., Hafezi, W., Kuhn, J. M., Oberleithner, H. & Shahin, V. Nuclear delivery mechanism of herpes simplex virus type 1 genome. J. Mol. Recognit. 24, 414–421 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Kerur, N. et al. IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe 9, 363–375 (2012).

    Article  CAS  Google Scholar 

  187. Singh, V. V. et al. Kaposi's sarcoma-associated herpesvirus latency in endothelial and B cells activates interferon γ-inducible protein 16 (IFI16) mediated inflammasomes. J. Virol. 87, 4417–4431 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Rathinam, V. A. & Fitzgerald, K. A. Innate immune sensing of DNA viruses. Virology 411, 153–162 (2011).

    Article  CAS  PubMed  Google Scholar 

  189. Johnson, K. E., Chikoti, L. & Chandran, B. HSV-1 Infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J. Virol. 87, 5005–5018 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nature Immunol. 11, 997–1004 (2010).

    Article  CAS  Google Scholar 

  191. Ansari, M. A. et al. Constitutive interferon-inducible protein 16-inflammasome activation during Epstein–Barr virus latency I, II, and III in B and epithelial cells. J. Virol. 87, 8606–8623 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Orzalli, M. H., DeLuca, N. A. & Knipe, D. M. Nuclear IFI16 induction of IRF-3 signaling during herpesviral infection and degradation of IFI16 by the viral ICP0 protein. Proc. Natl Acad. Sci. USA 109, E3008–E3017 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Domsic, J.F. et al. Molecular basis for oligomeric-DNA binding and episome maintenance by KSHV LANA. PLoS Pathog. 9, e1003672 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Correia, B. et al. Crystal structure of the Gamma-2 herpesvirus LANA DNA binding domain identifies charged surface residues which impact viral latency. PLoS Pathog. 9, e1003673 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Hellert, J. et al. A structural basis for BRD2/4-mediated host chromatin interaction and oligomer assembly of Kaposi Sarcoma-Associated herpesvirus and murine gammaherpesvirus LANA proteins. PLoS Pathog. 9, e1003640 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The author apologizes to his many colleagues for not citing numerous related studies owing to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul M. Lieberman.

Ethics declarations

Competing interests

The author declares an interest in a private company developing small molecule inhibitors of gammaherpesvirus latency.

PowerPoint slides

Glossary

Histone deacetylases

(HDACs). A family of enzymes that remove an acetyl group from lysine residues on histone tails. HDACs typically promote 'closed' (repressive) chromatin, and reverse the action of histone acetylases that promote 'open' (active) chromatin.

Bacmids

Large bacterial plasmids that can be used to propagate recombinant gammaherpesvirus genomes. They contain antibiotic resistance markers and fluorescent protein markers that greatly facilitate the engineering of site-directed mutations in gammaherpersvirus genomes.

Euchromatic

Regions of open chromatin that are more accessible to DNA-binding proteins and transcription initiation. By contrast, heterochromatic refers to 'closed' chromatin that is less accessible to transcription factors.

Zn hook

A structure that occurs when Zn mediates the interaction between two different molecules of the same protein through homotypic interactions, such that four amino acids (two from each protein monomer) form a cage to coordinate with a Zn atom at its centre.

Chromatin conformation capture

(3C). A method that can be used to measure the interaction between different DNA sites on the same or different chromosomes in vivo. It determines whether two different DNA regions are in close proximity to each other in vivo and is used to show that promoters and enhancers form interactions through DNA looping.

G-quadruplex

(also known as G-quartets or G4-DNA). DNA or RNA structures that can arise in G-rich stretches where four G bases form a planar structure that can be stacked to yield higher-order stable structures. G-quadruplexes can form between one (intramolecular) or more (intermolecular) DNA or RNA molecules.

DNA catenations

Structures that form when DNA strands are entangled, for example when two replication forks collide to terminate DNA replication. Some catenations, including hemicatenanes, form when the newly replicated DNA strands are entangled. Most DNA catenations can be decatenated by topoisomerases.

Unfolded protein response

A stress response that occurs in the endoplasmic reticulum (ER) when numerous proteins are misfolded or the ER is overwhelmed, as occurs during viral infection and during immunoglobulin production in plasma B cells.

Hypoxia

A condition of reduced oxygen that typically occurs in tumour cells that lack sufficient oxygenation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lieberman, P. Keeping it quiet: chromatin control of gammaherpesvirus latency. Nat Rev Microbiol 11, 863–875 (2013). https://doi.org/10.1038/nrmicro3135

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrmicro3135

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing