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Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription

View ORCID ProfileShasha Chong, Thomas G.W. Graham, Claire Dugast-Darzacq, Gina M. Dailey, View ORCID ProfileXavier Darzacq, View ORCID ProfileRobert Tjian
doi: https://doi.org/10.1101/2021.08.16.456551
Shasha Chong
1Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
2Howard Hughes Medical Institute, University of California, Berkeley, CA, USA
5Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA
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  • ORCID record for Shasha Chong
Thomas G.W. Graham
1Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
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Claire Dugast-Darzacq
1Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
4CIRM Center of Excellence, University of California, Berkeley, CA
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Gina M. Dailey
1Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
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Xavier Darzacq
1Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
4CIRM Center of Excellence, University of California, Berkeley, CA
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Robert Tjian
1Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
2Howard Hughes Medical Institute, University of California, Berkeley, CA, USA
3Li Ka Shing Center for Biomedical & Health Sciences, University of California, Berkeley, CA, USA
4CIRM Center of Excellence, University of California, Berkeley, CA
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  • For correspondence: jmlim@berkeley.edu
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Abstract

Gene activation by mammalian transcription factors (TFs) requires dynamic, multivalent, and selective interactions of their intrinsically disordered low-complexity domains (LCDs), but how such interactions mediate transcription remains unclear. It has been proposed that extensive LCD-LCD interactions culminating in liquid-liquid phase separation (LLPS) of TFs is the dominant mechanism underlying transactivation. Here, we investigated how tuning the amount and localization of LCD-LCD interactions in vivo affects transcription of endogenous human genes. Quantitative single-cell and single-molecule imaging reveals that the oncogenic TF EWS/FLI1 requires a finely tuned range of LCD-LCD interactions to efficiently activate target genes. Modest or more dramatic increases in LCD-LCD interactions toward putative LLPS repress EWS/FLI1-driven transcription in patient cells. Likewise, ectopically creating LCD-LCD interactions to sequester EWS/FLI1 into a bona fide LLPS compartment, the nucleolus, inhibits EWS/FLI1-driven transcription and oncogenic transformation. Our findings reveal fundamental principles underlying LCD-mediated transcription and suggest mislocalizing specific LCD-LCD interactions as a novel therapeutic strategy for targeting disease-causing TFs.

Competing Interest Statement

Robert Tjian and Xavier Darzacq are co-founders of Eikon Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted August 17, 2021.
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Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription
Shasha Chong, Thomas G.W. Graham, Claire Dugast-Darzacq, Gina M. Dailey, Xavier Darzacq, Robert Tjian
bioRxiv 2021.08.16.456551; doi: https://doi.org/10.1101/2021.08.16.456551
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Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription
Shasha Chong, Thomas G.W. Graham, Claire Dugast-Darzacq, Gina M. Dailey, Xavier Darzacq, Robert Tjian
bioRxiv 2021.08.16.456551; doi: https://doi.org/10.1101/2021.08.16.456551

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