title: Integrated analyses of genome-wide DNA occupancy and expression profiling identify key genes and pathways involved in cellular transformation by a Marek's disease virus oncoprotein, Meq.
abstract: Marek's disease (MD) is an economically significant disease in chickens that is 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 critically involved in viral oncogenicity, but only a few of its host target genes have been described, impeding our understanding of MDV-induced tumorigenesis. Using chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis, a high-confidence list of Meq binding sites in the chicken genome and a global transcriptome of Meq-responsive genes were generated. Meq binding sites were found to be enriched in the promoter regions of upregulated genes but not in those of downregulated genes. ChIP-seq was also performed for c-Jun, a known heterodimeric partner of Meq. The close location of binding sites of Meq and c-Jun 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 extracellular signal-regulated kinase /mitogen-activated protein kinase (ERK/MAPK), Jak-STAT, and ErbB pathways, which are critical for oncogenesis and/or include signaling mediators involved in apoptosis. Meq activates oncogenic signaling cascades by transcriptionally activating major kinases in the ERK/MAPK pathway and simultaneously repressing phosphatases, as verified using inhibitors of MEK and ERK1/2 in a cell proliferation assay. This study provides significant insights into the mechanistic basis of Meq-dependent cell transformation.
authors.affiliation: Comparative Medicine and Integrative Biology Program, College of Veterinary Medicine, Michigan State University, East Lansing, Michigan, USA.
authors.forename: Sugalesini
authors.initials: S
authors.lastname: Subramaniam
authors.forename: John
authors.initials: J
authors.lastname: Johnston
authors.forename: Likit
authors.initials: L
authors.lastname: Preeyanon
authors.forename: C Titus
authors.initials: CT
authors.lastname: Brown
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.forename: Hans H
authors.initials: HH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002472:Cell Transformation, Viral; D002645:Chickens; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions; D025922:Mardivirus / Q000472:pathogenicity*; D046228:Microarray Analysis; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014158:Transcription, Genetic; D037521:Virulence Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: C100369:Eco-Q protein, Gallid herpesvirus 2; D009856:Oncogene Proteins, Viral; D037521:Virulence Factors; D004247:DNA