Transcription Factor binding specificity is dictated by intrinsically disordered regions through distributed sensing

Transcription factors (TFs) that bind common DNA motifs­ in-vitro, occupy distinct sets of promoters in-vivo. Sequences outside the DNA binding domain (DBD) therefore contribute to binding site selection, but principles that guide this selection are still poorly understood. TFs are enriched with low complexity sequences that form intrinsically disordered regions (IDRs). Disordered domains have distinct characteristics compared to stably ordered domains, such as the ability to form multiple low affinity interactions with other IDRs. To address the question of whether IDRs contribute to TF binding-site selection, we considered two budding yeast stress regulators (MSN2 and Yap1) that contain a long (>500 aa) IDR outside their DBD. By mapping the binding profile of the wild-types and dozens of truncated mutants, we found that both factors still localize to the same set of promoters upon deletion of their DBD. This preference towards a selected group of promoters depends additively on a large number of weak and partially redundant determinants distributed throughout the entire IDR. Further, IDRs of distant homologous were successful in directing the TFs towards the wild-type selected promoters. We propose that TF search for their target binding sites through a two-step kinetics. First, TFs localize to broad DNA regions recognized by their IDRs. Subsequently, they use their DBD for binding their high-affinity binding motifs present within this broad region. By first sampling large DNA regions, IDRs can greatly accelerate TF search for their target genes in large genomes.