An intrinsically disordered region-mediated confinement state contributes to the dynamics and function of transcription factors

David A. Garcia, Thomas A. Johnson, Diego M. Presman, Gregory Fettweis, Kaustubh Wagh, Lorenzo Rinaldi, Diana A. Stavreva, Ville Paakinaho, Rikke A.M. Jensen, Susanne Mandrup, Arpita Upadhyaya*, Gordon L. Hager

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Transcription factors (TFs) regulate gene expression by binding to specific consensus motifs within the local chromatin context. The mechanisms by which TFs navigate the nuclear environment as they search for binding sites remain unclear. Here, we used single-molecule tracking and machine-learning-based classification to directly measure the nuclear mobility of the glucocorticoid receptor (GR) in live cells. We revealed two distinct and dynamic low-mobility populations. One accounts for specific binding to chromatin, while the other represents a confinement state that requires an intrinsically disordered region (IDR), implicated in liquid-liquid condensate subdomains. Further analysis showed that the dwell times of both subpopulations follow a power-law distribution, consistent with a broad distribution of affinities on the GR cistrome and interactome. Together, our data link IDRs with a confinement state that is functionally distinct from specific chromatin binding and modulates the transcriptional output by increasing the local concentration of TFs at specific sites. Garcia et al. use a systems-level approach to analyze single-molecule tracks of the glucocorticoid receptor. In addition to the known chromatin-bound state, the authors characterized an IDR-mediated, long-lived confined state consistent with liquid condensates that can amplify transcriptional output by increasing the local concentration of TFs at enhancer sites.

Original languageEnglish
JournalMolecular Cell
Volume81
Issue number7
Pages (from-to)1484-1498
ISSN1097-2765
DOIs
Publication statusPublished - 1. Apr 2021

Keywords

  • bi-exponential
  • chromatin binding
  • confinement
  • glucocorticoid receptor
  • GRdim
  • GRmon
  • intrinsically disordered regions
  • power-law
  • PPAR
  • single-molecule
  • transcription dynamics

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