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

Research output: Contribution to journalArticlepeer-review

Authors

  • Sharada Ramasubramanyan
  • Kay Osborn
  • Rajaei Al-Mohammad
  • Ijiel B Naranjo Perez-Fernandez
  • Nicolae Balan
  • Anja Godfrey
  • Harshil Patel
  • Gordon Peters
  • Richard G Jenner
  • Alison J Sinclair

Abstract

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.

Bibliographic note

© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Details

Original languageEnglish
Pages (from-to)3563-77
Number of pages15
JournalNucleic Acids Research
Volume43
Issue number7
Early online date16 Mar 2015
Publication statusPublished - 20 Apr 2015

Keywords

  • Base Sequence, Cell Line, Chromatin Immunoprecipitation, DNA Primers, Gene Expression Regulation, Viral, Herpesvirus 4, Human, Humans, Polymerase Chain Reaction, Regulatory Sequences, Nucleic Acid, Trans-Activators, Transcriptome