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Transcription factors use a unique combination of cofactors to potentiate different promoter-dependent steps in transcription

View ORCID ProfileCharles C Bell, Laure Talarmain, Laura Scolamiero, Enid YN Lam, Ching-Seng Ang, Omer Gilan, View ORCID ProfileMark A Dawson
doi: https://doi.org/10.1101/2022.10.25.513774
Charles C Bell
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
2Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia
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  • ORCID record for Charles C Bell
  • For correspondence: mark.dawson@petermac.org charles.bell@petermac.org
Laure Talarmain
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
2Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia
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Laura Scolamiero
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
2Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia
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Enid YN Lam
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
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Ching-Seng Ang
3Bio21 Mass Spectrometry and Proteomics Facility, The University of Melbourne, Parkville, VIC, Australia
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Omer Gilan
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
4Australian Centre for Blood Diseases, Monash University, VIC, Australia
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Mark A Dawson
1Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
2Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia
5Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
6Centre for Cancer Research, University of Melbourne, VIC, Australia
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  • ORCID record for Mark A Dawson
  • For correspondence: mark.dawson@petermac.org charles.bell@petermac.org
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Abstract

Transcription factors use DNA binding domains to recognise specific sequences and transactivation domains to recruit the cofactor proteins necessary for transcription. However, how specific cofactors contribute to transactivation at different genes remains unclear. Here, we couple Gal4-transactivation assays with comparative CRISPR-Cas9 screens to identify the cofactors required by nine different transcription factors and nine different core promoters in human cells. We classify cofactors as ubiquitous or specific, discover novel transcriptional co-dependencies and demonstrate that submodules within large co-activator complexes, such as the tail 2 and kinase modules of Mediator, facilitate transcriptional elongation. Rather than displaying discrete mechanisms of action, we discover that each TF requires a unique combination of cofactors, which influence its ability to potentiate distinct steps in the transcriptional process. Our findings help reconcile models of cofactor-promoter compatibility by demonstrating that transcription at different classes of promoters is constrained by either initiation or pause release. These differences dictate cofactor compatibility and the dynamic range of gene expression. Overall, our screens provide insight into TF-cofactor relationships and their ability to potentiate different steps in transcription at different classes of promoters.

Competing Interest Statement

M.A.D. has been a member of advisory boards for GSK, CTX CRC, Storm Therapeutics, Celgene, and Cambridge Epigenetix and receives research funding from Pfizer.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 25, 2022.
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Transcription factors use a unique combination of cofactors to potentiate different promoter-dependent steps in transcription
Charles C Bell, Laure Talarmain, Laura Scolamiero, Enid YN Lam, Ching-Seng Ang, Omer Gilan, Mark A Dawson
bioRxiv 2022.10.25.513774; doi: https://doi.org/10.1101/2022.10.25.513774
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Transcription factors use a unique combination of cofactors to potentiate different promoter-dependent steps in transcription
Charles C Bell, Laure Talarmain, Laura Scolamiero, Enid YN Lam, Ching-Seng Ang, Omer Gilan, Mark A Dawson
bioRxiv 2022.10.25.513774; doi: https://doi.org/10.1101/2022.10.25.513774

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