title: Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression.
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.
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Sharada
authors.initials: S
authors.lastname: Ramasubramanyan
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Kay
authors.initials: K
authors.lastname: Osborn
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Rajaei
authors.initials: R
authors.lastname: Al-Mohammad
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Ijiel B
authors.initials: IB
authors.lastname: Naranjo Perez-Fernandez
authors.affiliation: School of Cancer Sciences, The University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zuo
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Nicolae
authors.initials: N
authors.lastname: Balan
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.
authors.forename: Anja
authors.initials: A
authors.lastname: Godfrey
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Harshil
authors.initials: H
authors.lastname: Patel
authors.affiliation: Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.affiliation: School of Cancer Sciences, The University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Rowe
authors.affiliation: UCL Cancer Institute and MRC Centre for Medical Molecular Virology, Paul O'Gorman Building, University College London, London W1CE 6BT, UK.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Jenner
authors.affiliation: School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK a.j.sinclair@sussex.ac.uk.
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Sinclair
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D015967:Gene Expression Regulation, Viral / Q000502:physiology*; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D016133:Polymerase Chain Reaction; D012045:Regulatory Sequences, Nucleic Acid; D015534:Trans-Activators / Q000502:physiology*; D059467:Transcriptome
chemical_list: C063676:BZLF1 protein, Herpesvirus 4, Human; D017931:DNA Primers; D015534:Trans-Activators