A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform
Open accessPublished version of a preprint
Abstract
Mammalian switch/sucrose nonfermenting (mSWI/SNF) chromatin remodeling complexes modulate DNA accessibility and gene expression; however, their genomic targeting mechanisms remain incompletely understood. Here, we identify SWIFT [SWI/SNF immunoglobulin fold (Ig-fold) for transcription factor interactions], a conserved transcription factor (TF) binding domain on the SMARCD subunits. SWIFT is necessary and sufficient for direct engagement with the transactivation domain of the PU.1 TF. A single amino acid mutation disrupts PU.1-mSWI/SNF binding, impairs complex targeting, and attenuates oncogenic transcription and proliferation in PU.1-dependent human cancer cells. Dominant expression of the SWIFT domain in isolation sequesters TFs from mSWI/SNF and poisons TF-“addicted” cancer cells. Finally, TFs across diverse families interact with SMARCD paralog-specific SWIFT domains. These results define a major mechanism of cell type– and disease-specific mSWI/SNF chromatin targeting and inform approaches toward therapeutic modulation.
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- Authors
- Jain, S. U., Williamson, K. E., Ying, A. W., Turner, A. M., Jiang, R. J., Raval, S., So, K., Allison, M. J., Sankar, A., Sáme Guerra, D. D., Lin, Y., Jiang, Z., Mashtalir, N., Rohrs, H. W., Lichti, C. F., Muir, T. W., Papanastasiou, M., Paulo, J. A., Gygi, S. P., Gross, M. L., & Kadoch, C.
- Affiliations
- Harvard University (US)
- Broad Institute (US)
- Washington University in St. Louis (US)
- Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
- Princeton University (US)
- Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
- Corresponding author
- Kadoch, Cigall
- ORCID
- Venue
- Science
- Published
- 2026-04-02
- Volume
- 392
- Issue
- 6793
- Pages
- eaeb3627-eaeb3627
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC13276876
- OpenAlex
- W7117872459
- Cited by
- 11
- References
- 14
- Citations by year
- 2026: 10 · 2025: 1
- FWCI
- 20.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Science (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Institutes of Health (1DP2CA195762, 5R01CA259365, R01AG079283, R24GM136766, K99CA237855, R01GM132129, R35 GM156406, GM067945)
- Howard Hughes Medical Institute (Investigator)
- American Association for Cancer Research (RSG-14-051-01-DMC, John and Elizabeth Leonard Family Foundation Basic Cancer Research Fellowship)
- Pew Stewart Scholars in Cancer Research Award American Cancer Society Research Scholar Award (N/A)
- Mark Foundation For Cancer Research (Emerging Leader Award)
- National Science Foundation Graduate Research Fellowship Program (GRFP)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- SWI/SNF complex, immunoglobulin-like domains, transcription factor binding, PU.1, chromatin targeting, cancer therapy, transcriptional regulation
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