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

• 成果类型: Article
• 署名作者: Jain, Siddhant U.; Williamson, Kaylyn E.; Ying, Alexander W.; Turner, Aasha M.; Jiang, Ruidong Jerry; Raval, Shaunak; So, Kevin; Allison, Maxwell J.; Sankar, Akshay; Same Guerra, Daniel D.; Lin, Yutong; Jiang, Zhe; Mashtalir, Nazar; Rohrs, Henry W.; Lichti, Cheryl F.; Muir, Tom W.; Papanastasiou, Malvina; Paulo, Joao A.; Gygi, Steven P.; Gross, Michael L.; Kadoch, Cigall
• 署名单位: Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Washington University (WUSTL); Princeton University; Washington University (WUSTL); Washington University (WUSTL); Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeb3627
• 发表日期: 2026-04-02
• 页码: eaeb3627
• 关键词: CHROMATIN-REMODELING COMPLEX; LINKS HISTONE ACETYLATION; SMALL-CELL CARCINOMA; large-scale; expression; cancer; BRG1; phosphorylation; repression; subunit

摘要

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.