Kinetic profiling of the c-Myc transcriptome and bioinformatic analysis of repressed gene promoters

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 two-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 data set 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 transcriptional of c-Myc. We describe activation several by©2 c-Myc novel are 0 findings well 1 1 understood, L and a present n d how e tools s c-Myc B for i represses further oc s data i an e even mining. ne c greater Although . number the of mechanisms genes remains of incompletely described. One mechanism involves the binding of c-Myc to other, positively acting transcription factors and interfering with their activities. We D identified o n rapid-response o t d i s t genes r i b likely u t e 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.