Journal of Virology-2018-Wood-e00716-18.full.pdf (1.26 MB)
Enhancer control of MicroRNA miR-155 expression in EpsteinBarr virus-infected B cells
Version 2 2023-06-12, 07:23
Version 1 2023-06-09, 14:15
journal contribution
posted on 2023-06-12, 07:23 authored by David WoodDavid Wood, Thomas Carvell, Andrea Gunnell, Opeoluwa O Ojeniyi, Cameron Osborne, Michelle WestMichelle WestThe oncogenic microRNA miR-155 is the most frequently upregulated miRNA in Epstein-Barr virus (EBV)-positive B cell malignancies and is upregulated in other non-viral lymphomas. Both the EBV nuclear antigen 2 (EBNA2), and B cell transcription factor, interferon regulatory factor 4 (IRF4) are known to activate transcription of the host cell gene from which miR-155 is processed (miR-155HG, BIC). EBNA2 also activates IRF4 transcription indicating that EBV may upregulate miR-155 through direct and indirect mechanisms. The mechanism of transcriptional regulation of IRF4 and miR-155HG by EBNA2 however has not been defined. We demonstrate that EBNA2 can activate IRF4 and miR-155HG expression through specific upstream enhancers that are dependent on the Notch signaling transcription factor RBPJ, a known binding partner of EBNA2. We demonstrate that in addition to activation of the miR-155HG promoter, IRF4 can also activate miR-155HG via the upstream enhancer also targeted by EBNA2. Gene editing to remove the EBNA2- and IRF4-responsive miR-155HG enhancer located 60 kb upstream of miR-155HG led to reduced miR155HG expression in EBV-infected cells. Our data therefore demonstrate that specific RBPJ-dependent enhancers regulate the IRF4-miR-155 expression network and play a key role in the maintenance of miR-155 expression in EBV-infected B cells. These findings provide important insights that will improve our understanding of miR-155 control in B cell malignancies.
Funding
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/\
Gene deregulation in lymphoma: uncovering mechanisms and pathways exploited by Epstein-Barr virus; G1700; LEUKAEMIA AND LYMPHOMA RESEARCH; 15024
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- Published
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Journal
Journal of VirologyISSN
0022-538XPublisher
American Society for MicrobiologyExternal DOI
Issue
19Volume
92Page range
1Article number
e000716-18Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Haematology Research Group Publications
- Genome Damage and Stability Centre Publications
- Gene Expression Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-07-26First Open Access (FOA) Date
2018-07-26First Compliant Deposit (FCD) Date
2018-07-25Usage metrics
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