|Brown, C. Titus|
Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 7/22/2012
Publication Date: 7/22/2012
Citation: Subramaniam, S., Brown, C., Niikura, M., Cheng, H.H. 2012. Genome-wide identification of host genes directly regulated by Marek’s disease virus (MDV) oncoprotein Meq. Meeting Abstract. American Society for Virology 31st Annual Meeting July 21-25, 2012, Madison, Wisconsin. Workshop No. 19-4 Interpretive Summary:
Technical Abstract: Marek's disease (MD) is a contagious lymphoproliferative and neurotropic disease of poultry caused by Marek's disease virus (MDV), an oncogenic alphaherpesvirus. Despite the use of vaccines, the field strains of MDV continue to evolve, resulting in unpredictable disease outbreaks. Therefore, understanding the molecular basis for oncogenesis is of both fundamental and agricultural importance. MDV oncogenicity is largely attributed to the bZIP transcription factor Meq, which homodimerizes and heterodimerizes with c-Jun and other bZIP proteins. Our major goal is to gain a comprehensive understanding of host genes and proteins directly regulated by Meq. We used an immortalized chicken embryo fibroblast cell line (DF-1) transfected with Meq as our model. To identify genes directly regulated by Meq, DNA fractions bound by Meq or c-Jun were enriched using anti-Meq and anti-c-Jun antibodies followed by high-throughput sequencing (ChIP-seq). ChIP-seq analysis identified a total of 15,576 and 8,545 genomic regions bound to Meq or c-Jun, respectively, with 978 and 1694 genes within 2 Kb up-stream, respectively. Motif analysis revealed significant known and unknown DNA binding motifs. Microarray expression data showed 1,829 genes differentially expressed (p<0.05) between DF-1 and DF-1-Meq. Integrating ChIP-seq and microarray datasets revealed 186 candidate genes directly regulated by Meq. Functional analysis showed that Meq transforms the chicken cells via the c-Jun pathway with several b-ZIP and zinc-finger genes as Meq targets. These results were further confirmed in vivo using actual tumors from infected birds to gain higher confidence. Conclusion: This study is the first report to provide a global view of all genes directly regulated by Meq in vitro. Furthermore, it shows that Meq imparts transforming potential not only via the Jun-pathway but also through several cellular metabolic pathways.