Beyond motif recognition: Specificity of human transcription factors in yeast

This raises the question of how TFs distinguish specific targets from the many potential sites in the genome. To investigate determinants of binding specificity beyond the cognate motif and cofactor influences, we measured the binding of 60 human TFs across the budding yeast genome.

Although human TFs robustly recognized their motifs, they displayed strong selectivity in site occupancy. Nucleosome abundance explained this selectivity only in part: among the 5-20% of motif sites that were bound, a substantial fraction remained nucleosome covered. Furthermore, TFs recognizing similar motif sequences independently localized to distinct subsets of sites within different promoters.