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

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Abstrakt

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.

OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind81
Udgave nummer7
Sider (fra-til)1484-1498
ISSN1097-2765
DOI
StatusUdgivet - 1. apr. 2021

Bibliografisk note

Funding Information:
We thank Tatiana Karpova and David Ball from the Optical Microscopy Core at the NCI, NIH for assistance in imaging and data processing. We thank Luke Lavis (Janelia Research Campus) for providing HALO dyes. This research was supported (in part) by the Intramural Research Program of the NIH , National Cancer Institute , Center for Cancer Research . D.M.P. was supported by CONICET . V.P. was supported by the Academy of Finland , the Cancer Foundation Finland , and the Sigrid Jusélius Foundation . R.A.M.J. was supported by the Vissing Foundation , the William Demant Foundation , the Knud Højgaard Foundation , the Frimodt-Heineke Foundation , the Director Ib Henriksen Foundation , and the Ove and Edith Buhl Olesen Memorial Foundation . S.M. acknowledges support from the Danish Independent Research Council | Natural Sciences . A.U. acknowledges support from the NCI-UMD Cancer Technology Partnership and the awards NSF PHY 1607645 and NSF PHY 1806903 .

Publisher Copyright:
© 2021

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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