title: Different promoter affinities account for specificity in MYC-dependent gene regulation.
abstract: Enhanced expression of the MYC transcription factor is observed in the majority of tumors. Two seemingly conflicting models have been proposed for its function: one proposes that MYC enhances expression of all genes, while the other model suggests gene-specific regulation. Here, we have explored the hypothesis that specific gene expression profiles arise since promoters differ in affinity for MYC and high-affinity promoters are fully occupied by physiological levels of MYC. We determined cellular MYC levels and used RNA- and ChIP-sequencing to correlate promoter occupancy with gene expression at different concentrations of MYC. Mathematical modeling showed that binding affinities for interactions of MYC with DNA and with core promoter-bound factors, such as WDR5, are sufficient to explain promoter occupancies observed in vivo. Importantly, promoter affinity stratifies different biological processes that are regulated by MYC, explaining why tumor-specific MYC levels induce specific gene expression programs and alter defined biological properties of cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lorenzin
authors.affiliation: Group Mathematical Modeling of Cellular Processes, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Benary
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Apoorva
authors.initials: A
authors.lastname: Baluapuri
authors.affiliation: Core Unit Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Walz
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.|Rudolf-Virchow-Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Lisa Anna
authors.initials: LA
authors.lastname: Jung
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: von Eyss
authors.affiliation: Rudolf-Virchow-Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kisker
authors.affiliation: Group Mathematical Modeling of Cellular Processes, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Würzburg, Germany.
authors.forename: Elmar
authors.identifier: 0000-0002-5299-6335
authors.initials: E
authors.lastname: Wolf
mesh_terms: D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000378:metabolism*; D004847:Epithelial Cells / Q000502:physiology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008962:Models, Theoretical; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D004247:DNA
keywords: ChIP-sequencing; MIZ1; MYC; WDR5; cancer biology; cell biology; human; mathematical modeling; mouse; promoter affinity