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Intrinsically disordered regions as facilitators of the transcription factor target search

Nature Reviews Genetics volume 26, pages 424–435 (2025)Cite this article

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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.

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Fig. 1: Characteristics of TF IDRs across life.
Fig. 2: Models of the determinants governing transcription factor binding specificity.
Fig. 3: Models of the dynamics of the transcription factor target search process.
Fig. 4: Challenges with computational sequence analysis of IDRs.
Fig. 5: Experimental approaches for identifying functional TF IDR grammars.
Fig. 6: Possible mechanisms underlying IDR-based TF target specificity.

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Authors and Affiliations

  1. School of Science, Constructor University, Bremen, Germany

    Felix Jonas

  2. Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel

    Yoav Navon & Naama Barkai

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  1. Felix Jonas
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  2. Yoav Navon
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Contributions

All authors researched the literature for the article. All authors contributed substantially to discussion of the content. F.J. and N.B. wrote the article. F.J. and N.B. reviewed and/or edited the manuscript before submission.

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Correspondence to Felix Jonas or Naama Barkai.

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Nature Reviews Genetics thanks Alex Holehouse; H. Courtney Hodges, who co-reviewed with Katerina Cermakova; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Biomolecular condensates

Membrane-less intracellular compartments that can contain proteins and nucleic acids and are often formed through phase separation with multivalent interactions between the constituents.

Degrons

Short peptide sequences (3–10 amino acids) that recruit E3 ligases and trigger degradation by the ubiquitin–proteasome system.

Diffusion coefficient

Variable that describes the velocity of a transciption factor (TF) when diffusing through the nucleus.

Mutational robustness

Property of a gene related to the number of mutations necessary to perturb the function of the encoded protein.

Residence time

The length of time that a DNA-binding protein is bound to DNA. The mean residence time is often used to describe the dissociation reaction using first-order kinetics.

Stickers-and-spacers model

Model to explain the biophysical behaviour of intrinsically disordered regions (IDRs) containing hydrophobic residues (stickers) dispersed in a hydrophilic environment (spacer). The stickers interact with each other while the spacers provide flexibility to the interaction.

Super-enhancers

Group of enhancers (regulatory elements in higher eukaryotes) in close proximity to each other that have a higher propensity to bind transcription factors, recruit the mediator and promote transcription than individual enhancers.

Yeast-1-hybrid

Experimental set-up consisting of a potential DNA-binding protein (DBP) and its partner DNA sequence. The DBP is attached to an activation domain and expressed in yeast, which also contains the respective DNA sequence upstream of a reporter gene (for example, GFP), so that the DBP binding triggers reporter gene expression.

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Jonas, F., Navon, Y. & Barkai, N. Intrinsically disordered regions as facilitators of the transcription factor target search. Nat Rev Genet 26, 424–435 (2025). https://doi.org/10.1038/s41576-025-00816-3

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