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.DOI: http://dx.doi.org/10.7554/eLife.15161.001

Mathematical modelling of promoter occupancies in MYC-dependent gene regulation

“…The impact that changes of these dissociation constants have on occupancies was comprehensively explored in our earlier study [11]. In contrast to the dissociation constants, total numbers of molecules and binding sites are certainly cell type specific and are varied in our analysis.…”

“…For instance, their karyotype and/or the fraction of E-boxes in their genome may deviate due to single-nucleotide polymorphisms (SNPs), larger structural variations, segmental deletions or copy number variations, to name a few [16][17][18][19]. We here present an extended analysis of our published mathematical model of MYC-DNA-binding [11] to demonstrate that the insights gained in the investigation of U2OS cells may be generalized to other human cell types as well.…”

“…More recent experiments using chromatin-immunoprecipitation (ChIP) and ChIP-sequencing experiments [6][7][8][9] demonstrated that MYC binds to almost all promoters, enhancers and intergenic sites with an open chromatin structure, independent of the presence of E-boxes [10,11]. Despite this global DNA binding, MYC-dependent tumours seem to harbour a specific set of up-and down-regulated MYC target genes.…”

“…In our recent study, we proposed that the divergent hypotheses can be reconciled in the new hypothesis that specific gene expression profiles arise from different affinities of MYC-DNA binding [11]. We used a mathematical modelling approach in combination with extensive experimental data to show that differences in affinity are sufficient to explain the distinct promoter occupancies observed in ChIP-sequencing experiments for physiological and tumour-specific MYC concentrations.…”

“…This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. [11]; in brief, MYC can reversibly bind to either consensus E-boxes or unspecific binding sites on the DNA. B) Impact of total MYC levels on occupancies of E-boxes (red curves) and unspecific binding (blue curves) sites shown for particular combinations of genome sizes and E-box frequencies.…”