In mammalian cells, the MYC oncoprotein binds to thousands of promoters1,2,3,4. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes1. 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 value5,6,7. 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 elongation8. Third, complex formation with MIZ1 (also known as ZBTB17)9 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.
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This work was funded by the Deutsche Forschungsgemeinschaft (DFG) through grants 222/5-3 and 222/12-1 (to M.E.), by a stipend of the graduate college 1048 (“Molecular basis of organ development in vertebrates” to S.W.) and through the DFG Research Center for Experimental Biomedicine (to E.W.). M.T. was supported by grants from the Institut National Du Cancer (INCa) and by the Ligue National Contre le Cancer (Equipe Labellisée). O.S. and J.M. are funded by a Cancer Research UK core grant and a European Research Council investigator grant, “Coloncan”. We thank Y. L. Lee and T. Poh for help with ChIP-sequencing, F. Finkernagel for help with the bioinformatic analysis, A. Au for help with mouse experiments, B. Lüscher for critical reading of the manuscript and D. Levens for providing data before publication.
Extended data figures
Extended data tables
Myc- and Myc/Miz1-bound genes in murine fibroblasts, T-lymphoma cells and pancreatic tumour cells. "+" indicates promoters (-1 kb to +0.5 kb) containing a MACS-called peak (FDR<0.1), "-" indicates promoters without Myc or Myc/Miz1 binding site.
Oligonucleotides used in the study.
About this article
Cell Death & Differentiation (2019)