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

Cell Cycle. 2011 Jul 1;10(13):2184-96. doi: 10.4161/cc.10.13.16249. Epub 2011 Jul 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Cell Line
  • Citric Acid Cycle / physiology
  • Computational Biology / methods*
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Microarray Analysis
  • Multigene Family
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Rats
  • Signal Transduction / physiology
  • Tamoxifen / pharmacology
  • Transcriptome*

Substances

  • Antineoplastic Agents, Hormonal
  • Proto-Oncogene Proteins c-myc
  • Tamoxifen