Gunnell et al 2016.pdf (2.16 MB)
RUNX super-enhancer control through the Notch pathway by Epstein-Barr virus transcription factors regulates B cell growth
journal contribution
posted on 2023-06-09, 00:43 authored by Andrea Gunnell, Helen WebbHelen Webb, David WoodDavid Wood, Michael J McClellan, Billy Wichaidit, Bettina Kempkes, Richard G Jenner, Cameron Osborne, Paul J Farrell, Michelle WestMichelle WestIn 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.
Funding
How does Epstein-Barr virus contribute to the development of Burkitt's and other B-cell lymphomas?; G0902; LEUKAEMIA AND LYMPHOMA RESEARCH; 12035
Elucidating the regulation and function of the cell-cycle regulator RGC-32 in Epstein-Barr virus transformed cells; G1149; MRC-MEDICAL RESEARCH COUNCIL; MR/K01952X/\
Regulation and function of RUNX1 and RUNX3 in human B cells; G1197; LEUKAEMIA AND LYMPHOMA RESEARCH; 13032
History
Publication status
- Published
File Version
- Published version
Journal
Nucleic Acids ResearchISSN
0305-1048Publisher
Oxford University PressExternal DOI
Issue
10Volume
44Page range
4636-4650Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Haematology Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-03-31First Open Access (FOA) Date
2016-03-31First Compliant Deposit (FCD) Date
2016-03-31Usage metrics
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