Intrinsically disordered regions as facilitators of the transcription factor target search

Abstract

Transcription factors (TFs) contribute to organismal development and function by regulating gene expression. Despite decades of research, the factors determining the specificity and speed at which eukaryotic TFs detect their target binding sites remain poorly understood. Recent studies have pointed to intrinsically disordered regions (IDRs) within TFs as key regulators of the process by which TFs find their target sites on DNA (the TF target search). However, IDRs are challenging to study because they can confer specificity despite low sequence complexity and can be functionally conserved despite rapid sequence divergence. Nevertheless, emerging computational and experimental approaches are beginning to elucidate the sequence–function relationship within the IDRs of TFs. Additional insights are informing potential mechanisms underlying the IDR-directed search for the DNA targets of TFs, including incorporation into biomolecular condensates, facilitating TF co-localization, and the hypothesis that IDRs recognize and directly interact with specific genomic regions. Intrinsically disordered domains (IDRs) are increasingly appreciated as important components of protein function. This Perspective discusses the emerging evidence for IDRs from transcription factors as contributors to the transcription factor target search process, as well as the challenges associated with studying these regions.