Intrinsically Disordered Regions Direct Transcription Factor In Vivo Binding Specificity

Transcription factors (TFs) that bind common DNA motifs in vitro occupy distinct sets of promoters in vivo, raising the question of how binding specificity is achieved. TFs are enriched with intrinsically disordered regions (IDRs). Such regions commonly form promiscuous interactions, yet their unique properties might also benefit specific binding-site selection. We examine this using Msn2 and Yap1, TFs of distinct families that contain long IDRs outside their DNA-binding domains. We find that these IDRs are both necessary and sufficient for localizing to the majority of target promoters. This IDR-directed binding does not depend on any localized domain but results from a multitude of weak determinants distributed throughout the entire IDR sequence. Furthermore, IDR specificity is conserved between distant orthologs, suggesting direct interaction with multiple promoters. We propose that distribution of sensing determinants along extended IDRs accelerates binding-site detection by rapidly localizing TFs to broad DNA regions surrounding these sites. [Display omitted] •Transcription factors (TFs) bind a selected subset of their motif-containing promoters•Long intrinsically disordered regions (IDRs) guide TF promoter selection in vivo•Promoter recognition depends on multiple determinants distributed along the entire IDR•IDRs may accelerate the TF search for target promoters by recognizing broad DNA regions Transcription factors (TFs) bind only a subset of their motif-containing promoters. Brodsky and Jana et al. find that promoter selection is dictated by multiple specificity determinants distributed across long intrinsically disordered regions (IDRs) encoded within the TF sequence. IDR-guided specificity may accelerate binding-site recognition by an initial detection of broad DNA regions.