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

Wood, C David, Carvell, Thomas, Gunnell, Andrea, Ojeniyi, Opeoluwa O, Osborne, Cameron and West, Michelle J (2018) Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells. Journal of Virology. ISSN 0022-538X

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Abstract

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.

Item Type: Article
Keywords: microRNA, cancer, virus, enhancer, transcription
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Gene Expression Research Group
Genome Damage and Stability Centre
Subjects: Q Science > QP Physiology > QP0501 Animal biochemistry > QP0551 Proteins, amino acids, etc. > QP0552 Special proteins (other than amino acids, enzymes, or hormones), A-Z > QP0552.T6 Transcription Factors
Q Science > QP Physiology > QP0501 Animal biochemistry > QP0620 Nucleic acids
Q Science > QR Microbiology > QR0355 Virology
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens > RC0261 Cancer and other malignant neoplasms > RC0268.4 Genetic aspects. Cancer genes
Depositing User: Michelle West
Date Deposited: 26 Jul 2018 08:26
Last Modified: 26 Jul 2018 08:26
URI: http://srodev.sussex.ac.uk/id/eprint/77382

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Project NameSussex Project NumberFunderFunder Ref
Gene deregulation in lymphoma: uncovering mechanisms and pathways exploited by Epstein-Barr virusG1700LEUKAEMIA AND LYMPHOMA RESEARCH15024
Elucidating the regulation and function of the cell-cycle regulator RGC-32 in Epstein-Barr virus transformed cellsG1149MRC-MEDICAL RESEARCH COUNCILMR/K01952X/\