Epstein-Barr virus induces global changes in cellular mRNA isoform usage that are important for the maintenance of latency.


Oncogenic viruses promote cell proliferation through the dramatic reorganization of host transcriptomes. In addition to regulating mRNA abundance, changes in mRNA isoform usage can have a profound impact on the protein output of the transcriptome. Using Epstein-Barr virus (EBV) transformation of primary B cells, we have studied the ability of an oncogenic virus to alter the mRNA isoform profile of its host. Using the algorithm called SplicerEX with two complementary Affymetrix microarray platforms, we uncovered 433 mRNA isoform changes regulated by EBV during B-cell transformation. These changes were largely orthogonal with the 2,163 mRNA abundance changes observed during transformation, such that less than one-third of mRNAs changing at the level of isoform also changed in overall abundance. While we observed no preference for a mechanistic class of mRNA isoform change, we detected a significant shortening of 3' untranslated regions and exclusion of cassette exons in EBV-transformed cells relative to uninfected B cells. Gene ontology analysis of the mRNA isoform changes revealed significant enrichment in nucleic acid binding proteins. We validated several of these isoform changes and were intrigued by those in two mRNAs encoding the proteins XBP1 and TCF4, which have both been shown to bind and activate the promoter of the major EBV lytic trans-activator BZLF1. Our studies indicate that EBV latent infection promotes the usage of mRNA isoforms of XBP1 and TCF4 that restrict BZLF1 activation. Therefore, characterization of global changes in mRNA isoform usage during EBV infection identifies a new mechanism for the maintenance of latent infection.





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Publication Info

Homa, Nicholas J, Raul Salinas, Eleonora Forte, Timothy J Robinson, Mariano A Garcia-Blanco and Micah A Luftig (2013). Epstein-Barr virus induces global changes in cellular mRNA isoform usage that are important for the maintenance of latency. Journal of virology, 87(22). pp. 12291–12301. 10.1128/jvi.02464-13 Retrieved from https://hdl.handle.net/10161/24735.

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Raul Salinas

Research Associate, Senior

Micah Alan Luftig

Professor of Molecular Genetics and Microbiology

The Luftig laboratory studies viruses that cause cancer with an overarching goal of defining the basic molecular mechanisms underlying pathogenesis and leveraging these findings for diagnostic value and therapeutic intervention. Our work primarily focuses on the common herpesvirus, Epstein-Barr virus (EBV). This virus latently infects virtually all adults worldwide being acquired early in life. In the immune suppressed, EBV promotes lymphomas in the B cells that it naturally infects. However, EBV can also infect epithelial cells and other lymphocytes contributing to human cancers as wide-ranging as nasopharyngeal and gastric carcinoma to aggressive NK/T-cell, Burkitt, and Hodgkin lymphomas. Overall, EBV contributes to approximately 2% of all human cancers worldwide leading to nearly 200,000 deaths annually.

We use cutting-edge, cross-disciplinary and highly collaborative approaches to characterize the temporal dynamics and single cell heterogeneity of EBV infection. With these strategies, we aim to discover fundamental molecular circuits underlying transcriptional control, viral manipulation of host signaling pathways, and metabolic regulation that collectively influence infected cell fate decisions. By understanding the nature of viral control of infected host cells, we are also well positioned to discover vulnerabilities in EBV-associated diseases and characterize new therapeutic interventions in cell-based and pre-clinical animal models.

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