Order through disorder: The role of intrinsically disordered regions in transcription factor binding specificity

Transcription factors (TFs) must bind at specific genomic locations to accurately regulate gene expression. The ability of TFs to recognize specific DNA sequence motifs arises from the inherent preferences of their globular DNA-binding domains (DBDs). Yet, these preferences are insufficient to explain the in vivo TF binding site selection. TFs are enriched with intrinsically disordered regions (IDRs), most of which are poorly characterized. While not generally considered as determinants of TF binding specificity, IDRs guide protein-protein interactions within transcriptional condensates, and multiple examples exist in which short IDRs flanking the DBD contribute to binding specificity via direct contact with the DNA. We recently reported that long IDRs, present away from the DBD, act as major specificity determinants at the genomic scale. Here, we discuss mechanisms through which IDRs contribute to DNA binding specificity, highlighting the role of long IDRs in dictating the in vivo binding site selection.