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The viral and cellular microRNA targetome in lymphoblastoid cell lines

Item Type:Article
Title:The viral and cellular microRNA targetome in lymphoblastoid cell lines
Creators Name:Skalsky, R.L. and Corcoran, D.L. and Gottwein, E. and Frank, C.L. and Kang, D. and Hafner, M. and Nusbaum, J.D. and Feederle, R. and Delecluse, H.J. and Luftig, M.A. and Tuschl, T. and Ohler, U. and Cullen, B.R.
Abstract:Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus linked to a number of B cell cancers and lymphoproliferative disorders. During latent infection, EBV expresses 25 viral pre-microRNAs (miRNAs) and induces the expression of specific host miRNAs, such as miR-155 and miR-21, which potentially play a role in viral oncogenesis. To date, only a limited number of EBV miRNA targets have been identified; thus, the role of EBV miRNAs in viral pathogenesis and/or lymphomagenesis is not well defined. Here, we used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) combined with deep sequencing and computational analysis to comprehensively examine the viral and cellular miRNA targetome in EBV strain B95-8-infected lymphoblastoid cell lines (LCLs). We identified 7,827 miRNA-interaction sites in 3,492 cellular 3'UTRs. 531 of these sites contained seed matches to viral miRNAs. 24 PAR-CLIP-identified miRNA:3'UTR interactions were confirmed by reporter assays. Our results reveal that EBV miRNAs predominantly target cellular transcripts during latent infection, thereby manipulating the host environment. Furthermore, targets of EBV miRNAs are involved in multiple cellular processes that are directly relevant to viral infection, including innate immunity, cell survival, and cell proliferation. Finally, we present evidence that myc-regulated host miRNAs from the miR-17/92 cluster can regulate latent viral gene expression. This comprehensive survey of the miRNA targetome in EBV-infected B cells represents a key step towards defining the functions of EBV-encoded miRNAs, and potentially, identifying novel therapeutic targets for EBV-associated malignancies.
Keywords:3 Untranslated Regions, B-Lymphocytes, Epstein-Barr Virus Infections, Human Herpesvirus 4, Lymphoproliferative Disorders, MicroRNAs, Tumor Cell Line, Viral Cell Transformation, Virus Latency
Source:PLoS Pathogens
Publisher:Public Library of Science
Page Range:e1002484
Date:26 January 2012
Official Publication:https://doi.org/10.1371/journal.ppat.1002484
PubMed:View item in PubMed

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