Journal
MOLECULAR CELL
Volume 81, Issue 7, Pages 1484-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.01.013
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Funding
- NIH, National Cancer Institute, Center for Cancer Research
- CONICET
- Academy of Finland
- Cancer Foundation Finland
- Sigrid Juselius Foundation
- Vissing Foundation
- William Demant Foundation
- Knud Hojgaard Foundation
- Frimodt-Heineke Foundation
- Henriksen Foundation
- Ove and Edith Buhl Olesen Memorial Foundation
- Danish Independent Research Council \ Natural Sciences
- NCI-UMD Cancer Technology Partnership
- [NSF PHY 1607645]
- [NSF PHY 1806903]
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Our study revealed two distinct and dynamic low-mobility populations of transcription factors in the nucleus, one associated with specific chromatin binding and the other with a confinement state linked to liquid-liquid condensate subdomains. Further analysis showed that the dwell times of these populations follow a power-law distribution, consistent with a broad distribution of affinities on the transcription factor's cistrome and interactome.
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.
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