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Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression.

  • Ramasubramanyan, Sharada1
  • Osborn, Kay1
  • Al-Mohammad, Rajaei1
  • Naranjo Perez-Fernandez, Ijiel B1
  • Zuo, Jianmin2
  • Balan, Nicolae1
  • Godfrey, Anja1
  • Patel, Harshil3
  • Peters, Gordon3
  • Rowe, Martin2
  • Jenner, Richard G4
  • Sinclair, Alison J5
  • 1 School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
  • 2 School of Cancer Sciences, The University of Birmingham, Birmingham B15 2TT, UK.
  • 3 Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
  • 4 UCL Cancer Institute and MRC Centre for Medical Molecular Virology, Paul O'Gorman Building, University College London, London W1CE 6BT, UK.
  • 5 School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK [email protected]
Published Article
Nucleic Acids Research
Oxford University Press
Publication Date
Apr 20, 2015
DOI: 10.1093/nar/gkv212
PMID: 25779048


Lytic replication of the human gamma herpes virus Epstein-Barr virus (EBV) is an essential prerequisite for the spread of the virus. Differential regulation of a limited number of cellular genes has been reported in B-cells during the viral lytic replication cycle. We asked whether a viral bZIP transcription factor, Zta (BZLF1, ZEBRA, EB1), drives some of these changes. Using genome-wide chromatin immunoprecipitation coupled to next-generation DNA sequencing (ChIP-seq) we established a map of Zta interactions across the human genome. Using sensitive transcriptome analyses we identified 2263 cellular genes whose expression is significantly changed during the EBV lytic replication cycle. Zta binds 278 of the regulated genes and the distribution of binding sites shows that Zta binds mostly to sites that are distal to transcription start sites. This differs from the prevailing view that Zta activates viral genes by binding exclusively at promoter elements. We show that a synthetic Zta binding element confers Zta regulation at a distance and that distal Zta binding sites from cellular genes can confer Zta-mediated regulation on a heterologous promoter. This leads us to propose that Zta directly reprograms the expression of cellular genes through distal elements.


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