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Different promoter affinities account for specificity in MYC-dependent gene regulation

Please always quote using this URN: urn:nbn:de:bvb:20-opus-162913
  • 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.show moreshow less

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Metadaten
Author: Francesca Lorenzin, Uwe Benary, Apoorva Baluapuri, Susanne Walz, Lisa Anna Jung, Björn von Eyss, Caroline Kisker, Jana Wolf, Martin Eilers, Elmar Wolf
URN:urn:nbn:de:bvb:20-opus-162913
Document Type:Journal article
Faculties:Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Fakultät für Biologie / Theodor-Boveri-Institut für Biowissenschaften
Fakultät für Biologie / Rudolf-Virchow-Zentrum
Language:English
Parent Title (English):eLife
Year of Completion:2016
Volume:5
Pagenumber:e15161
Source:eLife 2016;5:e15161. DOI: 10.7554/eLife.15161
DOI:https://doi.org/10.7554/eLife.15161
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=PMC4963202
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:ChIP-sequencing; MIZ1; MYC; WDR5; cancer biology; cell biology; human; mathematical modeling; mouse; promoter affinity
Release Date:2018/08/22
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International