Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms
Open accessPublished version of a preprint
Abstract
Most human transcription factor (TF) genes encode multiple protein isoforms differing in DNA-binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators," both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.
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- Authors
- Lambourne, L., Mattioli, K., Santoso, C., Sheynkman, G., Inukai, S., Kaundal, B., Berenson, A., Spirohn-Fitzgerald, K., Bhattacharjee, A., Rothman, E., Shrestha, S., Laval, F., Carroll, B. S., Plassmeyer, S. P., Emenecker, R. J., Yang, Z., Bisht, D., Sewell, J. A., Li, G., Prasad, A., Phanor, S., Lane, R., Moyer, D. C., Hunt, T., Balcha, D., Gebbia, M., Twizere, J.-C., Hao, T., Holehouse, A. S., Frankish, A., Riback, J. A., Salomonis, N., Calderwood, M. A., Hill, D. E., Sahni, N., Vidal, M., Bulyk, M. L., & Fuxman Bass, J. I.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Boston University (US)
- The University of Texas MD Anderson Cancer Center (US)
- Cincinnati Children's Hospital Medical Center (US)
- Washington University in St. Louis (US)
- European Bioinformatics Institute (GB)
- University of Toronto (CA)
- University of Liège (BE)
- Corresponding author
- Mattioli, Kaia
- Sahni, Nidhi
- Vidal, Marc
- Bulyk, Martha L.
- ORCID
- Lambourne, Luke
- Mattioli, Kaia
- Santoso, Clarissa
- Sheynkman, Gloria
- Inukai, Sachi
- Kaundal, Babita
- Berenson, Anna
- Bhattacharjee, Anukana
- Laval, Florent
- Plassmeyer, Stephen P.
- Emenecker, Ryan J.
- Yang, Zhipeng
- Bisht, Deepa
- Sewell, Jared A.
- Li, Guangyuan
- Prasad, Anisa
- Phanor, Sabrina
- Lane, Ryan
- Moyer, Devlin C.
- Hunt, Toby
- Gebbia, Marinella
- Twizere, Jean-Claude
- Hao, Tong
- Holehouse, Alex S.
- Frankish, Adam
- Salomonis, Nathan
- Calderwood, Michael A.
- Hill, David E.
- Sahni, Nidhi
- Vidal, Marc
- Bulyk, Martha L.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2025-04
- Volume
- 85
- Issue
- 7
- Pages
- 1445-1466.e13
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC11014633
- OpenAlex
- W4408899521
- Cited by
- 42
- References
- 12
- Citations by year
- 2026: 23 · 2025: 15 · 2024: 3 · 2022: 1
- FWCI
- 10.49
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons-TMC (Texas Medical Center) (submittedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Open Repository and Bibliography (University of Liège) (submittedVersion, other-oa)
- Funders
- Belgian American Educational Foundation Inc
- Melanoma Research Foundation
- Wallonie-Bruxelles International
- Charles A King Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- transcription factor isoforms, alternative splicing, DNA binding, protein-protein interaction, transcriptional activation, subcellular localization, condensate formation, gene regulatory networks, differentiation, cancer
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