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Gunnell, A.* ; Webb, H.M.* ; Wood, C.D.* ; McClellan, M.J.* ; Wichaidit, B.* ; Kempkes, B. ; Jenner, R.G.* ; Osborne, C.* ; Farrell, P.J.* ; West, M.J.*

RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth.

Nucleic Acids Res. 44, 4636-4650 (2016)
Publ. Version/Full Text Supplement DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
In B cells infected by the cancer-associated Epstein-Barr virus (EBV), RUNX3 and RUNX1 transcription is manipulated to control cell growth. The EBV-encoded EBNA2 transcription factor (TF) activates RUNX3 transcription leading to RUNX3-mediated repression of the RUNX1 promoter and the relief of RUNX1-directed growth repression. We show that EBNA2 activates RUNX3 through a specific element within a -97 kb super-enhancer in a manner dependent on the expression of the Notch DNA-binding partner RBP-J. We also reveal that the EBV TFs EBNA3B and EBNA3C contribute to RUNX3 activation in EBV-infected cells by targeting the same element. Uncovering a counter-regulatory feed-forward step, we demonstrate EBNA2 activation of a RUNX1 super-enhancer (-139 to -250 kb) that results in low-level RUNX1 expression in cells refractory to RUNX1-mediated growth inhibition. EBNA2 activation of the RUNX1 super-enhancer is also dependent on RBP-J. Consistent with the context-dependent roles of EBNA3B and EBNA3C as activators or repressors, we find that these proteins negatively regulate the RUNX1 super-enhancer, curbing EBNA2 activation. Taken together our results reveal cell-type-specific exploitation of RUNX gene super-enhancers by multiple EBV TFs via the Notch pathway to fine tune RUNX3 and RUNX1 expression and manipulate B-cell growth.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Rbp-j-kappa; Signal Binding-protein; Nuclear Antigen-2; Burkitts-lymphoma; Down-regulation; 3c Binds; C-myc; Ebna-2; Domain; Dna
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Journal Nucleic Acids Research
Quellenangaben Volume: 44, Issue: 10, Pages: 4636-4650 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Oxford
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Gene Vector (AGV)