A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform
- Siddhant U. Jain
- Kaylyn E. Williamson
- Alexander W. Ying
- Aasha M. Turner
- Ruidong Jerry Jiang
- Shaunak Raval
- Kevin So
- Maxwell J. Allison
- Akshay Sankar
- Daniel D. Samé Guerra
- Yutong Lin
- Zhe Jiang
- Nazar Mashtalir
- Henry W. Rohrs
- Cheryl F. Lichti
- Tom W. Muir
- Malvina Papanastasiou
- Joao A. Paulo
- Steven P. Gygi
- Michael L. Gross
- Cigall Kadoch
2026-01-01
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.