A transcription factor by any other name - function beyond DNA binding and transactivation

Abstract Transcription is a highly regulated process, and transcription factors (TFs) play a central role in determining when and where transcription occurs. While TF binding is essential for transcription, recent observations shed new light on the relationship between sequence-specific DNA binding and transcription. TF occupancy frequently does not correlate with transcriptional output, and TFs can be recruited to sites where transcription is already active, blurring conventional notions of cause and effect. Moreover, the textbook view of defined domains for DNA binding and transcriptional regulation has begun to dissolve, with the roles of intrinsically disordered domains (IDRs) in both processes making it difficult to decipher how specificity and target regulation are controlled. Why are these disordered regions so common in TFs, and how do they contribute to the identity and function of these factors? In this review, we explore the nature of TFs and the consequences of their binding for cell state transitions. Where and when do they act to stimulate transcription, find their targets, and interface with signaling to propagate specific gene expression programs?