Recent experiments provide an unprecedented view of protein-DNA binding in yeast and human genomes at single-nucleotide resolution. These measurements, performed over large cell populations, show quite generally that sequence-specific transcription regulators with well-defined protein-DNA consensus motifs bind only a fraction among all consensus motifs present in the genome. Alternatively, proteins in vivo often bind DNA regions lacking known consensus sequences. The rules determining whether a consensus motif is functional remain incompletely understood. Here we predict that genomic background surrounding specific protein-DNA binding motifs statistically modulates the binding of sequence-specific transcription regulators to these motifs. In particular, we show that nonconsensus protein-DNA binding in yeast is statistically enhanced, on average, around functional Reb1 motifs that are bound as compared to nonfunctional Reb1 motifs that are unbound. The landscape of nonconsensus protein-DNA binding around functional CTCF motifs in human demonstrates a more complex behavior. In particular, human genomic regions characterized by the highest CTCF occupancy, show statistically reduced level of nonconsensus protein-DNA binding. Our findings suggest that nonconsensus protein-DNA binding is fine-tuned around functional binding sites using a variety of design strategies.
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