title: Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles.
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.
authors.affiliation: 1] Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [2].
authors.forename: Susanne
authors.initials: S
authors.lastname: Walz
authors.affiliation: 1] Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [2].
authors.forename: Francesca
authors.initials: F
authors.lastname: Lorenzin
authors.affiliation: CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Morton
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Wiese
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: von Eyss
authors.affiliation: Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Herold
authors.affiliation: Institute for Molecular Biology and Tumor Research (IMT), Emil-Mannkopff-Str.2, 35033 Marburg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Rycak
authors.affiliation: University of Bordeaux, IECB, ARNA laboratory, Equipe Labellisée Contre le Cancer, 33600 Pessac, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Dumay-Odelot
authors.affiliation: CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Saadia
authors.initials: S
authors.lastname: Karim
authors.affiliation: Institute for Genetics, Justus-Liebig-University, Heinrich-Buff-Ring 58, 35390 Giessen, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Bartkuhn
authors.affiliation: University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roels
authors.affiliation: University Hospital Tübingen, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, Otfried-Mueller-Strasse 10, 72076 Tübingen, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Wüstefeld
authors.affiliation: University Children's Hospital of Cologne, and Cologne Center for Molecular Medicine (CMMC), University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: University of Bordeaux, IECB, ARNA laboratory, Equipe Labellisée Contre le Cancer, 33600 Pessac, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Teichmann
authors.affiliation: 1] University Hospital Tübingen, Division of Translational Gastrointestinal Oncology, Department of Internal Medicine I, Otfried-Mueller-Strasse 10, 72076 Tübingen, Germany [2] Translational Gastrointestinal Oncology Group within the German Center for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Zender
authors.affiliation: DOE Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, California 94598, USA.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wei
authors.affiliation: CRUK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
authors.forename: Owen
authors.initials: O
authors.lastname: Sansom
authors.affiliation: 1] Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [2] Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str.2, 97080 Würzburg, Germany [3].
authors.forename: Elmar
authors.initials: E
authors.lastname: Wolf
authors.affiliation: 1] Theodor Boveri Institute, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany [2] Comprehensive Cancer Center Mainfranken, University of Würzburg, Josef-Schneider-Str. 6, 97080 Würzburg, Germany [3].
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics*; D024721:E-Box Elements / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012319:RNA Polymerase II / Q000378:metabolism; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D051741:Kruppel-Like Transcription Factors; C489427:MYC protein, human; C489428:Myc protein, mouse; D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D016271:Proto-Oncogene Proteins c-myc; C107961:ZBTB17 protein, human; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D012319:RNA Polymerase II