Different promoter affinities account for specificity in MYC-dependent gene regulation
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- 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 toEnhanced 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.…
Autor(en): | Francesca Lorenzin, Uwe Benary, Apoorva Baluapuri, Susanne Walz, Lisa Anna Jung, Björn von Eyss, Caroline Kisker, Jana Wolf, Martin Eilers, Elmar Wolf |
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URN: | urn:nbn:de:bvb:20-opus-162913 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften |
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften | |
Fakultät für Biologie / Rudolf-Virchow-Zentrum | |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | eLife |
Erscheinungsjahr: | 2016 |
Band / Jahrgang: | 5 |
Seitenangabe: | e15161 |
Originalveröffentlichung / Quelle: | eLife 2016;5:e15161. DOI: 10.7554/eLife.15161 |
DOI: | https://doi.org/10.7554/eLife.15161 |
PubMed-ID: | https://pubmed.ncbi.nlm.nih.gov/PMC4963202 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | ChIP-sequencing; MIZ1; MYC; WDR5; cancer biology; cell biology; human; mathematical modeling; mouse; promoter affinity |
Datum der Freischaltung: | 22.08.2018 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |