2. Academic Validation
  3. Unstructured transcription factor interactions enable emergent specificity

Unstructured transcription factor interactions enable emergent specificity

  • Science. 2026 Mar 19:eaeb6487. doi: 10.1126/science.aeb6487.
Abrar A Abidi 1 2,  Claudia Cattoglio 1 2,  Natalie N Tang 1,  Vinson B Fan 1,  Gina M Dailey 1,  Amir D Hay 1 2,  Prasanthi Kunamaneni 3,  Daniel E Milkie 4,  Xavier Darzacq 1,  Eric Betzig 1 2 4,  Robert Tjian # 1 2,  Thomas G W Graham # 1 2 3
Affiliations

Affiliations

  • 1 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
  • 2 Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, USA.
  • 3 Thomas C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA.
  • 4 Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
  • # Contributed equally.
PMID: 41855276 DOI: 10.1126/science.aeb6487
Abstract

How intrinsically disordered regions (IDRs) influence chromatin binding and nuclear organization of transcription factors (TFs) remains unclear. We employed proximity-assisted photoactivation (PAPA), a single-molecule protein-protein interaction sensor, to investigate how IDRs might influence TF interactions with each Other and with chromatin in live cells. We found that the Sp1 DNA binding domain (DBD) interacted poorly with chromatin and did not colocalize with Sp1. Weak interaction of the isolated IDR with full-length Sp1 was enhanced by fusion to various unrelated DBDs. Live imaging of Drosophila polytene chromosomes confirmed that an IDR could confer sharp locus specificity on an otherwise nonspecific DBD. These findings suggest that TF specificity emerges on chromatin when ensembles of diverse, unstructured interactions are scaffolded by transient DNA contacts.

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