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

Gunnell, Andrea, Webb, Helen M, Wood, David, McClellan, Michael J, Wichaidit, Billy, Kempkes, Bettina, Jenner, Richard G, Osborne, Cameron, Farrell, Paul J and West, Michelle J (2016) RUNXsuper-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth. Nucleic Acids Research. ISSN 0305-1048

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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.

Item Type: Article
Schools and Departments: Brighton and Sussex Medical School > Brighton and Sussex Medical School
Subjects: R Medicine > R Medicine (General)
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Depositing User: Nikoleta Kiapidou
Date Deposited: 17 Feb 2016 13:59
Last Modified: 07 Mar 2017 04:56
URI: http://sro.sussex.ac.uk/id/eprint/59678

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Project NameSussex Project NumberFunderFunder Ref
Elucidating the regulation and function of the cell-cycle regulator RGC-32 in Epstein-Barr virus transformed cellsG1149MRCMR/K01952X/\