TY - JOUR
T1 - A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform
AU - Jain, Siddhant U.
AU - Williamson, Kaylyn E.
AU - Ying, Alexander W.
AU - Turner, Aasha M.
AU - Jiang, Ruidong Jerry
AU - Raval, Shaunak
AU - So, Kevin
AU - Allison, Maxwell J.
AU - Sankar, Akshay
AU - Sáme Guerra, Daniel D.
AU - Lin, Yutong
AU - Jiang, Zhe
AU - Mashtalir, Nazar
AU - Rohrs, Henry W.
AU - Lichti, Cheryl F.
AU - Muir, Tom W.
AU - Papanastasiou, Malvina
AU - Paulo, Joao A.
AU - Gygi, Steven P.
AU - Gross, Michael L.
AU - Kadoch, Cigall
N1 - Publisher Copyright:
Copyright © 2026 the authors, some rights reserved;
PY - 2026/4/2
Y1 - 2026/4/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105035002350
U2 - 10.1126/science.aeb3627
DO - 10.1126/science.aeb3627
M3 - Article
C2 - 41477818
AN - SCOPUS:105035002350
SN - 0036-8075
VL - 392
JO - Science
JF - Science
IS - 6793
M1 - eaeb3627
ER -