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

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...

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Bibliographic Details
Published in:eLife 2016-07, Vol.5
Main Authors: Lorenzin, Francesca, Benary, Uwe, Baluapuri, Apoorva, Walz, Susanne, Jung, Lisa Anna, von Eyss, Björn, Kisker, Caroline, Wolf, Jana, Eilers, Martin, Wolf, Elmar
Format: Article
Language:English
Subjects:
Affinity
Cancer Biology
Cell Biology
Cell Line
ChIP-sequencing
Chromatin Immunoprecipitation
Deoxyribonucleic acid
DNA
DNA - metabolism
Epithelial Cells - physiology
Gene expression
Gene Expression Profiling
Gene Expression Regulation
Gene regulation
Genetic regulation
Humans
mathematical modeling
Mathematical models
MIZ1
Models, Theoretical
MYC
Myc protein
Observations
Ontology
Ordinary differential equations
promoter affinity
Promoter Regions, Genetic
Promoters
Promoters (Genetics)
Protein Binding
Proteins
Proto-Oncogene Proteins c-myc - metabolism
Ribonucleic acid
RNA
Sequence Analysis, DNA
Sequence Analysis, RNA
Transcription, Genetic
Tumors
WDR5
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.15161