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

Gunnell, Andrea, Webb, Helen M, Wood, David C, McClellan, Michael J, Wichaidit, Billy, Kempkes, Bettina, Richard, Jenner G, Cameron, Osborne, Farrell, Paul J and West, Michelle J (2016) RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth. Nucleic Acids Research, 44 (10). pp. 4636-4650. ISSN 0305-1048

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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
Keywords: Epstein-Barr virus Transcription RUNX lymphoma enhancer
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
Depositing User: Michelle West
Date Deposited: 31 Mar 2016 13:50
Last Modified: 13 Mar 2017 19:30

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