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Enhancer control of MicroRNA miR-155 expression in EpsteinBarr virus-infected B cells

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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 West
The 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

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Virology

ISSN

0022-538X

Publisher

American Society for Microbiology

Issue

19

Volume

92

Page range

1

Article number

e000716-18

Department 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

2018-07-26

First Open Access (FOA) Date

2018-07-26

First Compliant Deposit (FCD) Date

2018-07-25

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