A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform

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.