Siddhant U. Jain, Kaylyn E. Williamson, Alexander W. Ying, Aasha M. Turner, Ruidong 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, João A. Paulo, Steven P. Gygi, Michael L. Gross, Cigall Kadoch
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.