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Identification and functional characterization of transcriptional activators in human cells

View ORCID ProfileNader Alerasool, Zhen-Yuan Lin, View ORCID ProfileAnne-Claude Gingras, View ORCID ProfileMikko Taipale
doi: https://doi.org/10.1101/2021.07.30.454360
Nader Alerasool
1Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
2Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada
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Zhen-Yuan Lin
3Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
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Anne-Claude Gingras
1Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
3Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health System, Toronto, ON M5G 1X5, Canada
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Mikko Taipale
1Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
2Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada
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  • For correspondence: mikko.taipale@utoronto.ca
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SUMMARY

Transcription is orchestrated by thousands of transcription factors and chromatin-associated proteins, but how these are causally connected to transcriptional activation or repression is poorly understood. Here, we conduct an unbiased proteome-scale screen to systematically uncover human proteins that activate transcription in a natural chromatin context. We also identify potent transactivation domains among the hits. By combining interaction proteomics and chemical inhibitors, we delineate the preference of both known and novel transcriptional activators for specific co-activators, highlighting how even closely related TFs can function via distinct co-factors. Finally, we show that many novel activators are partners in fusion events in tumors and functionally characterize a myofibroma-associated fusion between SRF and C3orf62, a potent activator. SRF-C3orf62 activates transcription in a CBP/p300-dependent manner and promotes proliferative and myogenic transcriptional programs. Our work provides a functional catalogue of potent transactivators in the human proteome and a platform for discovering transcriptional regulators at genome scale.

Competing Interest Statement

University of Toronto has filed a provisional patent related to this work.

Footnotes

  • Lead Contact: Mikko Taipale

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 July 30, 2021.
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Identification and functional characterization of transcriptional activators in human cells
Nader Alerasool, Zhen-Yuan Lin, Anne-Claude Gingras, Mikko Taipale
bioRxiv 2021.07.30.454360; doi: https://doi.org/10.1101/2021.07.30.454360
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Identification and functional characterization of transcriptional activators in human cells
Nader Alerasool, Zhen-Yuan Lin, Anne-Claude Gingras, Mikko Taipale
bioRxiv 2021.07.30.454360; doi: https://doi.org/10.1101/2021.07.30.454360

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