Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells

Takayuki Murata, Yutaka Kondo, Atsuko Sugimoto, Daisuke Kawashima, Shinichi Saito, Hiroki Isomura, Teru Kanda, Tatsuya Tsurumi

Research output: Contribution to journalArticle

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Abstract

The Epstein-Barr virus (EBV) predominantly establishes latent infection in B cells, and the reactivation of the virus from latency is dependent on the expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), calcium ionophores, or histone deacetylase (HDAC) inhibitors. In some cell lines latently infected with EBV, an HDAC inhibitor alone can induce BZLF1 transcription, while the treatment does not enhance expression in other cell lines, such as B95-8 or Raji cells, suggesting unknown suppressive mechanisms besides histone deacetylation in those cells. Here, we found the epigenetic modification of the BZLF1 promoter in latent Raji cells by histone H3 lysine 27 trimethylation (H3K27me3), H3K9me2/me3, and H4K20me3. Levels of active markers such as histone acetylation and H3K4me3 were low in latent cells but increased upon reactivation. Treatment with 3-deazaneplanocin A (DZNep), an inhibitor of H3K27me3 and H4K20me3, significantly enhanced the BZLF1 transcription in Raji cells when in combination with an HDAC inhibitor, trichostatin A (TSA). The knockdown of Ezh2 or Suv420h1, histone methyltransferases for H3K27me3 or H4K20me3, respectively, further proved the suppression of Zp by the methylations. Taken together, the results indicate that H3K27 methylation and H4K20 methylation are involved, at least partly, in the maintenance of latency, and histone acetylation and H3K4 methylation correlate with the reactivation of the virus in Raji cells.

Original languageEnglish
Pages (from-to)4752-4761
Number of pages10
JournalJournal of Virology
Volume86
Issue number9
DOIs
Publication statusPublished - 01-05-2012

Fingerprint

Histone Code
Human herpesvirus 4
Human Herpesvirus 4
Epigenomics
histones
epigenetics
promoter regions
methylation
histone deacetylase
Histones
Methylation
Histone Deacetylase Inhibitors
acetylation
cells
Acetylation
trichostatin A
transcription (genetics)
cell lines
Virus Latency
Cell Line

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Murata, Takayuki ; Kondo, Yutaka ; Sugimoto, Atsuko ; Kawashima, Daisuke ; Saito, Shinichi ; Isomura, Hiroki ; Kanda, Teru ; Tsurumi, Tatsuya. / Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells. In: Journal of Virology. 2012 ; Vol. 86, No. 9. pp. 4752-4761.
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Murata, T, Kondo, Y, Sugimoto, A, Kawashima, D, Saito, S, Isomura, H, Kanda, T & Tsurumi, T 2012, 'Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells', Journal of Virology, vol. 86, no. 9, pp. 4752-4761. https://doi.org/10.1128/JVI.06768-11

Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells. / Murata, Takayuki; Kondo, Yutaka; Sugimoto, Atsuko; Kawashima, Daisuke; Saito, Shinichi; Isomura, Hiroki; Kanda, Teru; Tsurumi, Tatsuya.

In: Journal of Virology, Vol. 86, No. 9, 01.05.2012, p. 4752-4761.

Research output: Contribution to journalArticle

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T1 - Epigenetic histone modification of Epstein-Barr virus BZLF1 promoter during latency and reactivation in Raji cells

AU - Murata, Takayuki

AU - Kondo, Yutaka

AU - Sugimoto, Atsuko

AU - Kawashima, Daisuke

AU - Saito, Shinichi

AU - Isomura, Hiroki

AU - Kanda, Teru

AU - Tsurumi, Tatsuya

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N2 - The Epstein-Barr virus (EBV) predominantly establishes latent infection in B cells, and the reactivation of the virus from latency is dependent on the expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), calcium ionophores, or histone deacetylase (HDAC) inhibitors. In some cell lines latently infected with EBV, an HDAC inhibitor alone can induce BZLF1 transcription, while the treatment does not enhance expression in other cell lines, such as B95-8 or Raji cells, suggesting unknown suppressive mechanisms besides histone deacetylation in those cells. Here, we found the epigenetic modification of the BZLF1 promoter in latent Raji cells by histone H3 lysine 27 trimethylation (H3K27me3), H3K9me2/me3, and H4K20me3. Levels of active markers such as histone acetylation and H3K4me3 were low in latent cells but increased upon reactivation. Treatment with 3-deazaneplanocin A (DZNep), an inhibitor of H3K27me3 and H4K20me3, significantly enhanced the BZLF1 transcription in Raji cells when in combination with an HDAC inhibitor, trichostatin A (TSA). The knockdown of Ezh2 or Suv420h1, histone methyltransferases for H3K27me3 or H4K20me3, respectively, further proved the suppression of Zp by the methylations. Taken together, the results indicate that H3K27 methylation and H4K20 methylation are involved, at least partly, in the maintenance of latency, and histone acetylation and H3K4 methylation correlate with the reactivation of the virus in Raji cells.

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