Abstract
The human MYC proto-oncogene protein (MYC) is a transcription factor that plays a major role in the regulation of cell proliferation. Deregulation of MYC expression is often found in cancer. In the last years, several hypotheses have been proposed to explain cell type specific MYC target gene expression patterns despite genome wide DNA binding of MYC. In a recent publication, a mathematical modelling approach in combination with experimental data demonstrated that differences in MYC-DNA-binding affinity are sufficient to explain distinct promoter occupancies and allow stratification of distinct MYC-regulated biological processes at different MYC concentrations. Here, we extend the analysis of the published mathematical model of DNA-binding behaviour of MYC to demonstrate that the insights gained in the investigation of the human osteosarcoma cell line U2OS can be generalized to other human cell types.
Highlights
The human MYC gene codes for a transcription factor called Myc proto-oncogene protein that is involved in a variety of cellular processes, including regulation of cell proliferation [1, 2]
Two kinds of parameters are considered in the model: (I) dissociation constants (KEbox, KU) interpreted as inverse measures of affinity of MYC-enhancer box (E-box)-binding and unspecific MYC binding to DNA, respectively (Figure 1A), and (II) total numbers of molecules and binding sites ([MYCtotal], [Eboxtotal], [Utotal])
Cells may differ in the number of promoters with transcriptional capacity, for instance by restricting the frequency of E-boxes available for MYC binding
Summary
The human MYC gene codes for a transcription factor called Myc proto-oncogene protein (in the following abbreviated with MYC) that is involved in a variety of cellular processes, including regulation of cell proliferation [1, 2]. 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. Global changes in mRNA levels in this model are the consequence of physiological and metabolic changes induced by specific sets of regulated genes
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