Activation and Repression by Oncogenic MYC Shape Tumour-Specific Gene Expression Profiles

Nature. 2014 Jul 24;511(7510):483-7. doi: 10.1038/nature13473. Epub 2014 Jul 9.

Abstract

In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Down-Regulation / genetics*
  • E-Box Elements / genetics
  • Gene Expression Regulation, Neoplastic / genetics*
  • Genes, myc / genetics*
  • Humans
  • Kruppel-Like Transcription Factors / metabolism
  • Mice
  • Neoplasms / genetics*
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Inhibitors of Activated STAT / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Polymerase II / metabolism
  • Transcriptome*
  • Ubiquitin-Protein Ligases
  • Up-Regulation / genetics*

Substances

  • Kruppel-Like Transcription Factors
  • MYC protein, human
  • Myc protein, mouse
  • Nuclear Proteins
  • Protein Inhibitors of Activated STAT
  • Proto-Oncogene Proteins c-myc
  • ZBTB17 protein, human
  • Miz1 protein, mouse
  • Ubiquitin-Protein Ligases
  • RNA Polymerase II

Associated data

  • GEO/GSE44672