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

Sugalesini Subramaniam, John Johnston, Likit Preeyanon, Charles Brown, Hsing-Jien Kung, Hans H. Cheng

Research output: Contribution to journalArticle

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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 transcrip-tome 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.

Original languageEnglish (US)
Pages (from-to)9016-9029
Number of pages14
JournalJournal of Virology
Volume87
Issue number16
DOIs
StatePublished - Aug 2013

Fingerprint

Marek Disease
Mardivirus
Oncogene Proteins
Genome
Viruses
genome
DNA
binding sites
mitogen-activated protein kinase kinase
Chromatin Immunoprecipitation
Genes
Binding Sites
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
genes
carcinogenesis
chromatin
Chickens
Carcinogenesis

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

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. / Subramaniam, Sugalesini; Johnston, John; Preeyanon, Likit; Brown, Charles; Kung, Hsing-Jien; Cheng, Hans H.

In: Journal of Virology, Vol. 87, No. 16, 08.2013, p. 9016-9029.

Research output: Contribution to journalArticle

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