Integrated requirement of non-specific and sequence-specific DNA binding for transcriptional regulation by Myc (RNA-seq)

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 motif (E-box), and profiled their DNA-binding and gene-regulatory properties in cultured cells. Our data reveal that non-specific DNA binding is required for MYC to target genomic regulatory regions, and a prerequisite for sequence recognition; beyond merely stabilizing MYC onto select target loci, sequence-specific binding contributes to its precise positioning and – most unexpectedly – to transcriptional activity per se. Hence, seemingly promiscuous genome interaction profiles encompass diverse binding modalities and drive defined, sequence-dependent transcriptional responses. Mapping genomic distribution and transcriptional activity of Myc mutants proteins