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

Ramasubramanyan, Sharada, Osborn, Kay, Al-Mohammad, Rajaei, Naranjo Perez-Fernandez, Ijiel B, Zuo, Jianmin, Balan, Nicolae, Godfrey, Anja, Patel, Harshil, Peters, Gordon, Rowe, Martin, Jenner, Richard G and Sinclair, Alison J (2015) Epstein-Barr virus transcription factor Zta acts through distal regulatory elements to directly control cellular gene expression. Nucleic Acids Research, 43 (7). pp. 3563-3577. ISSN 0305-1048

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Q Science > QH Natural history > QH0301 Biology > QH0471 Reproduction
Q Science > QH Natural history > QH0301 Biology
Q Science > QR Microbiology > QR0355 Virology
Depositing User: Alison Sinclair
Date Deposited: 22 Apr 2015 15:27
Last Modified: 24 Mar 2017 14:36
URI: http://sro.sussex.ac.uk/id/eprint/53414

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