title: Kinetic profiling of the c-Myc transcriptome and bioinformatic analysis of repressed gene promoters.
abstract: Mammalian c-Myc is a member of a small family of three related proto-oncogenic transcription factors. c-Myc has an unusually broad array of regulatory functions, which include roles in cell cycle and apoptosis, a variety of metabolic functions, cell differentiation, senescence, and stem cell maintenance. c-Myc modulates the expression of a very large number of genes, but the magnitude of the majority of the regulatory effects is only 2-fold or less. c-Myc can both activate and repress the promoters of its target genes. Identification of genes directly regulated by c-Myc has been an enduring question in the field. We report here microarray expression profiling of a high resolution time course of c-Myc induction, using fibroblast cells in which c-Myc activity can be modulated from null to physiological. The c-Myc transcriptome dataset presented is the largest reported to date with 4,186 differentially regulated genes (1,826 upregulated, 2,360 downregulated, 1% FDR). The gene expression patterns fit well with the known biological functions of c-Myc. We describe several novel findings and present tools for further data mining. Although the mechanisms of transcriptional activation by c-Myc are well understood, how c-Myc represses an even greater number of genes remains incompletely described. One mechanism involves the binding of c-Myc to other, positively acting transcription factors, and interfering with their activities. We identified rapid-response genes likely to be direct c-Myc targets, and analyzed the promoters of the repressed genes to identify transcription factors that could be targets of c-Myc repression.
authors.affiliation: Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
authors.forename: Chui-Sun
authors.initials: CS
authors.lastname: Yap
authors.forename: Abigail L
authors.initials: AL
authors.lastname: Peterson
authors.forename: Gastone
authors.initials: G
authors.lastname: Castellani
authors.forename: John M
authors.initials: JM
authors.lastname: Sedivy
authors.forename: Nicola
authors.initials: N
authors.lastname: Neretti
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D002460:Cell Line; D002952:Citric Acid Cycle / Q000502:physiology; D019295:Computational Biology / Q000379:methods*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D046228:Microarray Analysis; D005810:Multigene Family; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D013629:Tamoxifen / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen