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McClellan, M.J.* ; Wood, C.D.* ; Ojeniyi, O.* ; Cooper, T.J.* ; Kanhere, A.* ; Arvey, A.* ; Webb, H.M.* ; Palermo, R.D.* ; Harth-Hertle, M.L. ; Kempkes, B. ; Jenner, R.G.* ; West, M.J.*

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming.

PLoS Pathog. 9:e1003636 (2013)
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Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Nuclear Antigen 3c ; Latent Membrane-protein ; Nuclear-protein-2 Acidic Domain ; Transformation In-vitro ; Signal-binding-protein ; Long-range Interaction ; Rbp-j-kappa ; Burkitts-lymphoma ; Growth Transformation ; Ebna-2-mediated Transactivation
Sprache englisch
Veröffentlichungsjahr 2013
HGF-Berichtsjahr 2013
ISSN (print) / ISBN 1553-7366
e-ISSN 1553-7374
Zeitschrift PLoS Pathogens
Quellenangaben Band: 9, Heft: 9, Seiten: , Artikelnummer: e1003636 Supplement: ,
Verlag Public Library of Science (PLoS)
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Gene Vector (AGV)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Immune Response and Infection
PSP-Element(e) G-501500-002
PubMed ID 24068937
DOI 10.1371/journal.ppat.1003636
WOS ID WOS:000324922300045
Scopus ID 84884685804
Erfassungsdatum 2013-10-16
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