Identification and functional characterization of transcriptional activators in human cells
Open accessPublished version of a preprint
Abstract
Transcription is orchestrated by thousands of transcription factors (TFs) and chromatin-associated proteins, but how these are causally connected to transcriptional activation is poorly understood. Here, we conduct an unbiased proteome-scale screen to systematically uncover human proteins that activate transcription in a natural chromatin context. By combining interaction proteomics and chemical inhibitors, we delineate the preference of these transcriptional activators for specific co-activators, highlighting how even closely related TFs can function via distinct cofactors. We also identify potent transactivation domains among the hits and use AlphaFold2 to predict and experimentally validate interaction interfaces of two activation domains with BRD4. 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 p300-dependent activator. Our work provides a functional catalog of potent transactivators in the human proteome and a platform for discovering transcriptional regulators at genome scale.
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The observation that p300 catalytic activity does not contribute to destabilization is inconsistent with a model by which histone acetylation reduces nucleosome-DNA affinity to facilitate TF binding.
“appears inconsistent with a model by which histone acetylation reduces nucleosome-DNA affinity to facilitate TF binding29,49,50”
From Single-molecule states link transcription factor binding to gene expression (2024) · cites this paper as [29]
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- Authors
- Alerasool, N., Leng, H., Lin, Z.-Y., Gingras, A.-C., & Taipale, M.
- Affiliations
- University of Toronto (CA)
- Mount Sinai Hospital (CA)
- Corresponding author
- Gingras, Anne-Claude
- Taipale, Mikko
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2022-02
- Volume
- 82
- Issue
- 3
- Pages
- 677-695.e7
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W4221095165
- Cited by
- 120
- References
- 16
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 31 · 2023: 29 · 2022: 17 · 2021: 1
- FWCI
- 8.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Genome Canada (OGI-139)
- Ontario Genomics (OGI‐139)
- Government of Ontario (OGI-139)
- University of Toronto
- Canadian Institutes of Health Research (PJT175277, FDN143301)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- transcriptional activator, transcription factors, transcriptional coactivator, transactivation domain, BRD4, protein-protein interfaces, chemical inhibitors, SRF, P300, myofibroma, chromatin, transcriptional regulation
- MeSH terms
- Bromodomain Containing Proteins, Animals, Cell Line, Humans, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Cell Cycle Proteins, K562 Cells, Proteome, Serum Response Factor, Intercellular Signaling Peptides and Proteins, Proteomics, NIH 3T3 Cells, Myofibroma, Mice, HEK293 Cells
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