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

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Title: RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth.
Authors: Gunnell, A
Webb, HM
Wood, CD
McClellan, MJ
Wichaidit, B
Kempkes, B
Jenner, RG
Osborne, C
Farrell, PJ
West, MJ
Item Type: Journal Article
Abstract: 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.
Issue Date: 15-Feb-2016
Date of Acceptance: 1-Feb-2016
URI: http://hdl.handle.net/10044/1/29936
DOI: http://dx.doi.org/10.1093/nar/gkw085
ISSN: 1362-4962
Publisher: Oxford University Press (OUP)
Start Page: 4636
End Page: 4650
Journal / Book Title: Nucleic Acids Research
Volume: 44
Issue: 10
Copyright Statement: © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Leukaemia & Lymphoma Research "Beating Blood Cancers"
Funder's Grant Number: 13032
Keywords: Developmental Biology
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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