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

Chong, Shasha and Graham, Thomas G. W. and Dugast-Darzacq, Claire and Dailey, Gina M. and Darzacq, Xavier and Tjian, Robert (2021) Tuning levels of low-complexity domain interactions to modulate endogenous oncogenic transcription. . (Unpublished)

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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.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Chong, Shasha0000-0002-5372-311X
Dugast-Darzacq, Claire0000-0001-8602-3534
Darzacq, Xavier0000-0003-2537-8395
Tjian, Robert0000-0003-0539-8217
Additional Information: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. This version posted August 17, 2021. We thank L. Lavis for providing fluorescent HaloTag ligands; Q. Zhu for help with molecular cloning; K. Adiga for help optimizing conditions of doxycycline induction; the CRL Flow Cytometry Facility and Molecular Imaging Center; A. Hansen, S. Teves, and members of Tjian/Darzacq labs for critical reading of the manuscript. This work was supported by the Jane Coffin Childs Memorial Fund for Medical Research (to TGWG), California Institute of Regenerative Medicine grant LA1-08013 (to XD), NIH grants UO1-EB021236 and U54-DK107980 (to XD), and the Howard Hughes Medical Institute (to RT). Author contributions: Conceptualization: RT, SC Funding acquisition: RT, XD, CDD Investigation: SC, TGWG, CDD, GMD, RT Software: SC, TGWG Visualization: SC, TGWG, CDD Supervision: RT Project administration: RT, SC Writing – original draft: SC, RT, TGWG, CDD Writing – review & editing: SC, RT, TGWG, CDD, XD. Competing interests: RT and XD are co-founders of Eikon Therapeutics.
Funding AgencyGrant Number
Jane Coffin Childs Memorial Fund for Medical ResearchUNSPECIFIED
California Institute of Regenerative MedicineLA1-08013
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Record Number:CaltechAUTHORS:20210821-004311309
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Official Citation: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:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110343
Deposited By: Tony Diaz
Deposited On:21 Aug 2021 17:30
Last Modified:16 Nov 2021 19:40

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