|SUBRAMANIAM, SUGALISINI - Michigan State University|
|JOHNSTON, JOHN - Michigan State University|
|PREEYANON, LIKIT - Michigan State University|
|BROWN, C. TITUS - Michigan State University|
|KUNG, HSING-JIEN - University Of California|
Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/31/2013
Publication Date: 6/5/2013
Publication URL: http://handle.nal.usda.gov/10113/57122
Citation: Subramaniam, S., Johnston, J., Preeyanon, L., Brown, C., Kung, H., Cheng, H.H. 2013. Integrated analyses of genome-wide DNA occupancy and expression profiling identify key genes and pathways involved in cellular transformation by the Marek's disease virus oncoprotein Meq. Journal of Virology. 87(16):9016-9029. Available at: http://jvi.asm.org/content/87/16/9016.full.
Interpretive Summary: Marek’s disease, a herpesvirus-induced T cell cancer of chickens, is one of the most serious disease problems facing the poultry industry. Efforts to control this infectious disease has been hampered by the lack of knownledge on how the virus promotes transformation (development of cancer). In this study, using a combination of genomic techniques, we identified genes and pathways directly regulated by the the viral oncoprotein named Meq. This information should lead to the selection of chickens with enhanced disease resistance as well as the generation of more effective vaccines.
Technical Abstract: Marek’s disease (MD) is an economically significant disease in chickens caused by the highly oncogenic Marek’s disease virus (MDV). A major unanswered question is the mechanism of MDV-induced tumor formation. Meq, a bZIP transcription factor discovered in the 1990s, is largely attributed for viral oncogenicity though only a few of host target genes have been described, which has impeded our understanding of MDV-induced tumorigenesis. Using a combination of ChIP-seq and microarray analysis, a high confidence list of Meq-binding sites and a global transcriptome of genes regulated by Meq was generated. The distribution of Meq binding sites was non-random across the chicken genome and was mostly enriched in the promoter regions. Furthermore, the binding sites were enriched in the promoter region in up-regulated genes, which was not the case for down-regulated genes. Combining the information from c-Jun binding sites, close proximity of Meq and c-Jun binding sites was noted, suggesting cooperativity between these two factors in modulating transcription. Pathway analysis indicated that Meq transcriptionally regulates many genes that are part of several signaling pathways including the ERK/MAPK, Jak-STAT, and ErbB pathways that are critical for oncogenesis and or signaling mediators involved in apoptosis. In addition, Meq activates oncogenic signaling cascades by transcriptionally activating major kinases in the ERK/MAPK pathway and simultaneously repressing phosphatases, which was verified using inhibitors to MEK and ERK1/2 in a cell proliferation assay. Taken together, our study provides significant insights on the mechanistic basis of how Meq could lead to malignant transformation.