Abstract
Eukaryotic transcription factors recognize specific DNA sequence motifs, but are also endowed with generic, non-specific DNA-binding activity: how these binding modes are integrated to determine select transcriptional outputs remains unresolved. We designed mutants of the MYC transcription factor bearing substitutions in residues that contact either the DNA backbone or specific bases within the consensus binding motif (E-box), and profiled their DNA-binding and gene-regulatory activities in murine cells. Our data reveal that non-specific DNA binding is required for MYC to engage onto active regulatory elements in the genome, preceding sequence recognition; beyond merely stabilizing MYC onto select target loci, sequence-specific binding contributes to its precise positioning and – most unexpectedly – to transcriptional activation per se. In particular, at any given binding intensity, promoters targeted via the cognate DNA motif were more frequently activated by MYC. Hence, seemingly promiscuous chromatin interaction profiles actually encompass diverse DNA-binding modalities, driving defined, sequence-dependent transcriptional responses.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Our original preprint was posted in bioRxiv by automatic transfer upon submission to the EMBO Journal. This resulted in posting of the main file but not of the Supplemental Figures: hence, we hereby resubmit a file with all the figures. As per EMBO J. nomenclature, the supplemnetal figures are labeled EV1 to EV5 and Appendix FigureS1. This is also how they are referred to in the text.