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Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells

C. David Wood, Thomas Carvell, Andrea Gunnell, Opeoluwa O. Ojeniyi, Cameron Osborne, Michelle J. West
doi: https://doi.org/10.1101/311886
C. David Wood
aSchool of Life Sciences, University of Sussex, Falmer, Brighton, UK
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Thomas Carvell
aSchool of Life Sciences, University of Sussex, Falmer, Brighton, UK
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Andrea Gunnell
aSchool of Life Sciences, University of Sussex, Falmer, Brighton, UK
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Opeoluwa O. Ojeniyi
aSchool of Life Sciences, University of Sussex, Falmer, Brighton, UK
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Cameron Osborne
bDepartment of Medical and Molecular Genetics, King’s College London School of Medicine, Guy’s Hospital, London, UK
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Michelle J. West
aSchool of Life Sciences, University of Sussex, Falmer, Brighton, UK
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  • For correspondence: m.j.west@sussex.ac.uk
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ABSTRACT

The oncogenic microRNA-155 (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.

IMPORTANCE MicroRNA-155 (miR-155) is expressed at high level in many human cancers particularly lymphomas. Epstein-Barr virus (EBV) infects human B cells and drives the development of numerous lymphomas. Two EBV-encoded genes (LMP1 and EBNA2) upregulate miR-155 expression and miR-155 expression is required for the growth of EBV-infected B cells. We show that the EBV transcription factor EBNA2 upregulates miR-155 expression by activating an enhancer upstream from the miR-155 host gene (miR-155HG) from which miR-155 is derived. We show that EBNA2 also indirectly activates miR-155 expression through enhancer-mediated activation of IRF4. IRF4 then activates both the miR-155HG promoter and the upstream enhancer, independently of EBNA2. Gene editing to remove the miR-155HG enhancer leads to a reduction in miR-155HG expression. We therefore identify enhancer-mediated activation of miR-155HG as a critical step in promoting B cell growth and a likely driver of lymphoma development.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 01, 2018.
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Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells
C. David Wood, Thomas Carvell, Andrea Gunnell, Opeoluwa O. Ojeniyi, Cameron Osborne, Michelle J. West
bioRxiv 311886; doi: https://doi.org/10.1101/311886
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Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells
C. David Wood, Thomas Carvell, Andrea Gunnell, Opeoluwa O. Ojeniyi, Cameron Osborne, Michelle J. West
bioRxiv 311886; doi: https://doi.org/10.1101/311886

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