Unstructured transcription factor interactions enable emergent specificity

Science 2026 Open access

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Authors: Abrar A Abidi, Claudia Cattoglio, Natalie N. Tang, Vinson B. Fan, Gina M. Dailey, Amir D. Hay, Prasanthi Kunamaneni, Daniel E. Milkie, Xavier Darzacq, Eric Betzig, Robert Tjian, Thomas G. W. Graham
DOI: 10.1126/science.aeb6487
Cited by: 12
References: 76

Abstract

How intrinsically disordered regions (IDRs) shape chromatin binding and nuclear organization of transcription factors (TFs) remains unclear. We used 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.

Fields of Study & Subjects

Genomics and Chromatin Dynamics Developmental Biology and Gene Regulation Retinal Development and Disorders

Publication details

Journal / source
Science
Publisher
American Association for the Advancement of Science (AAAS)
Volume
392
Issue
6801
Pages
eaeb6487–eaeb6487
Publication date
19 March 2026
Language
EN