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

Authors: Susanne Mandrup; Ville Paakinaho; Diana A. Stavreva; Thomas A. Johnson; Lorenzo Rinaldi; David A. Garcia; David A. Garcia; +8 Authors

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

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.

Keywords

intrinsically disordered regions, GRMON, Transcription Factors/genetics, GRDIM, CONFINEMENT, Receptors, Glucocorticoid/chemistry, Biochimie, biophysique & biologie moléculaire, PPAR, Mice, Receptors, Glucocorticoid, https://purl.org/becyt/ford/1.6, glucocorticoid receptor, Receptors, Glucocorticoid/genetics, BI-EXPONENTIAL, Animals, POWER-LAW, Transcription Factors/metabolism, SINGLE-MOLECULE, https://purl.org/becyt/ford/1, Molecular Biology, Receptors, Glucocorticoid/metabolism, CHROMATIN BINDING, GRmon, Intrinsically Disordered Proteins/metabolism, GRdim, chromatin binding, Cell Biology, Transcription Factors/chemistry, TRANSCRIPTION DYNAMICS, Life sciences, Rats, Intrinsically Disordered Proteins, Intrinsically Disordered Proteins/chemistry, power-law, confinement, GLUCOCORTICOID RECEPTOR, Sciences du vivant, Intrinsically Disordered Proteins/genetics, INTRINSICALLY DISORDERED REGIONS, Female, single-molecule, transcription dynamics, bi-exponential, Biochemistry, biophysics & molecular biology, Transcription Factors

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
114
Top 1%
Top 10%
Top 1%
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