Abstract
BackgroundThe Myc-Max heterodimer is a transcription factor that regulates expression of a large number of genes. Genome occupancy of Myc-Max is thought to be driven by Enhancer box (E-box) DNA elements, CACGTG or variants, to which the heterodimer binds in vitro.ResultsBy analyzing ChIP-Seq datasets, we demonstrate that the positions occupied by Myc-Max across the human genome correlate with the RNA polymerase II, Pol II, transcription machinery significantly better than with E-boxes. Metagene analyses show that in promoter regions, Myc is uniformly positioned about 100 bp upstream of essentially all promoter proximal paused polymerases with Max about 15 bp upstream of Myc. We re-evaluate the DNA binding properties of full length Myc-Max proteins. Electrophoretic mobility shift assay results demonstrate Myc-Max heterodimers display significant sequence preference, but have high affinity for any DNA. Quantification of the relative affinities of Myc-Max for all possible 8-mers using universal protein-binding microarray assays shows that sequences surrounding core 6-mers significantly affect binding. Compared to the in vitro sequence preferences, Myc-Max genomic occupancy measured by ChIP-Seq is largely, although not completely, independent of sequence specificity.ConclusionsWe quantified the affinity of Myc-Max to all possible 8-mers and compared this with the sites of Myc binding across the human genome. Our results indicate that the genomic occupancy of Myc cannot be explained by its intrinsic DNA specificity and suggest that the transcription machinery and associated promoter accessibility play a predominant role in Myc recruitment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0482-3) contains supplementary material, which is available to authorized users.
Highlights
The Myc-Max heterodimer is a transcription factor that regulates expression of a large number of genes
Genome occupancy of Myc and Max correlates with Pol II Using the UCSC Genome Browser [31] and ChIP-Seq datasets generated from HeLa cells [32] with antibodies stringently validated by the ENCODE project [33], occupancies of Myc and Max visually correlate with Pol II better than with the Enhancer box (E-box) element CACGTG
A closer view of one such gene demonstrates that Myc and Max reside in a position between the two peaks of Pol II (Figure 1B)
Summary
The Myc-Max heterodimer is a transcription factor that regulates expression of a large number of genes. Genome occupancy of Myc-Max is thought to be driven by Enhancer box (E-box) DNA elements, CACGTG or variants, to which the heterodimer binds in vitro. Myc was initially identified as a proto-oncoprotein and subsequently demonstrated to be a global regulator of transcription [1,2,3,4,5,6]. A significant advancement in understanding Myc function was achieved by two comprehensive studies from the Young and Levens labs [5,6]. Both used inducible systems to show that Myc, when switched on, utilized existing expression programs and globally amplified transcription leading to an increase in the majority of expressed mRNAs. One study concluded that induction of
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