Comparative cofactor screens show the influence of transactivation domains and core promoters on the mechanisms of transcription
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Abstract
Eukaryotic transcription factors (TFs) activate gene expression by recruiting cofactors to promoters. However, the relationships between TFs, promoters and their associated cofactors remain poorly understood. Here we combine GAL4-transactivation assays with comparative CRISPR-Cas9 screens to identify the cofactors used by nine different TFs and core promoters in human cells. Using this dataset, we associate TFs with cofactors, classify cofactors as ubiquitous or specific and discover transcriptional co-dependencies. Through a reductionistic, comparative approach, we demonstrate that TFs do not display discrete mechanisms of activation. Instead, each TF depends on a unique combination of cofactors, which influences distinct steps in transcription. By contrast, the influence of core promoters appears relatively discrete. Different promoter classes are constrained by either initiation or pause-release, which influences their dynamic range and compatibility with cofactors. Overall, our comparative cofactor screens characterize the interplay between TFs, cofactors and core promoters, identifying general principles by which they influence transcription.
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33/38 factors included in this study contained repressor domains.
“This model is also supported by the observation that 33/38 factors included in this study contained repressor domains49 and by recent data demonstrating that different co-factors of the same TF modulate different steps in a transcriptional cycle.55”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [55]
The Establishing a transcription factor-based screening system section describes nine transcription factors and the activation domains used in the screens. Neither it nor the other retrieved passages reports that 33 of 38 factors contained repressor domains (searched: “33/38 factors repressor domains,” “repressor domains 38 transcription factors,” and “repressor”). (LLM, conf=0.76)
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Design principles of cell-state-specific enhancers in hematopoiesis
Frömel, R., Rühle, J., Bernal Martinez, A., Szu-Tu, C., Pacheco Pastor, F., Martinez-Corral, R., & Velten, L. (2025) · Cell · doi:10.1016/j.cell.2025.04.017 · Cited by 29 · see citing works
- Authors
- Bell, C. C., Balic, J. J., Talarmain, L., Gillespie, A., Scolamiero, L., Lam, E. Y. N., Ang, C.-S., Faulkner, G. J., Gilan, O., & Dawson, M. A.
- Affiliations
- The University of Queensland (AU)
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Corresponding author
- Bell, Charles C.
- Dawson, Mark A.
- ORCID
- Venue
- Nature Genetics
- Published
- 2024-05-20
- Volume
- 56
- Issue
- 6
- Pages
- 1181-1192
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W4398139183
- Cited by
- 30
- References
- 10
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 4 · 2023: 4
- FWCI
- 3.36
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Department of Health | National Health and Medical Research Council (1196749)
- Howard Hughes Medical Institute (55008729)
- Department of Education and Training | Australian Research Council (DP220103927)
- Cancer Council Victoria (200603)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- transcription factors, transcriptional cofactors, core promoter, transactivation domain, CRISPR-Cas9 screen, transcription initiation, pause release, cofactor specificity, human cells
- MeSH terms
- Gene Expression Regulation, Humans, Promoter Regions, Genetic, Transcription Factors, Transcription, Genetic, Transcriptional Activation, CRISPR-Cas Systems
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