Contribution of myocyte enhancer factor 2 family transcription factors to BZLF1 expression in epstein-barr virus reactivation from Latency

Takayuki Murata, Yohei Narita, Atsuko Sugimoto, Daisuke Kawashima, Teru Kanda, Tatsuya Tsurumi

Research output: Contribution to journalArticle

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Abstract

Reactivation of Epstein-Barr virus (EBV) from latency is dependent on expression of the viral transactivator BZLF1 protein, whose promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers. Using a reporter assay system, we screened for factors that can activate Zp and isolated genes, including those encoding MEF2B, KLF4, and some cellular b-Zip family transcription factors. After confirming their importance and functional binding sites in reporter assays, we prepared recombinant EBV-BAC, in which the binding sites were mutated. Interestingly, the MEF2 mutant virus produced very low levels of BRLF1, another transactivator of EBV, in addition to BZLF1 in HEK293 cells. The virus failed to induce a subset of early genes, such as that encoding BALF5, upon lytic induction, and accordingly, could not replicate to produce progeny viruses in HEK293 cells, but this restriction could be completely lifted by exogenous supply of BRLF1, together with BZLF1. In B cells, induction of BZLF1 by chemical inducers was inhibited by point mutations in the ZII or the three SP1/KLF binding sites of EBV-BAC Zp, while leaky BZLF1 expression was less affected. Mutation of MEF2 sites severely impaired both spontaneous and induced expression of not only BZLF1, but also BRLF1 in comparison to wild-type or revertant virus cases.Wealso observed that MEF2 mutant EBV featured relatively high repressive histone methylation, such as H3K27me3, but CpGDNAmethylation levels were comparable around Zp and the BRLF1 promoter (Rp). These findings shed light on BZLF1 expression and EBV reactivation from latency.

Original languageEnglish
Pages (from-to)10148-10162
Number of pages15
JournalJournal of Virology
Volume87
Issue number18
DOIs
Publication statusPublished - 05-09-2013

Fingerprint

MEF2 Transcription Factors
Virus Latency
Human herpesvirus 4
Human Herpesvirus 4
myocytes
Transcription Factors
transcription factors
Viruses
binding sites
viruses
Trans-Activators
HEK293 Cells
Binding Sites
promoter regions
mutants
assays
point mutation
Point Mutation
histones
methylation

All Science Journal Classification (ASJC) codes

  • Immunology
  • Virology

Cite this

Murata, Takayuki ; Narita, Yohei ; Sugimoto, Atsuko ; Kawashima, Daisuke ; Kanda, Teru ; Tsurumi, Tatsuya. / Contribution of myocyte enhancer factor 2 family transcription factors to BZLF1 expression in epstein-barr virus reactivation from Latency. In: Journal of Virology. 2013 ; Vol. 87, No. 18. pp. 10148-10162.
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Contribution of myocyte enhancer factor 2 family transcription factors to BZLF1 expression in epstein-barr virus reactivation from Latency. / Murata, Takayuki; Narita, Yohei; Sugimoto, Atsuko; Kawashima, Daisuke; Kanda, Teru; Tsurumi, Tatsuya.

In: Journal of Virology, Vol. 87, No. 18, 05.09.2013, p. 10148-10162.

Research output: Contribution to journalArticle

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