该研究团队在SMARCD亚基上发现了一个保守的转录因子（TF）结合域SWIFT [SWI/SNF免疫球蛋白折叠（Ig-fold）用于转录因子相互作用]。SWIFT对于直接参与PU.1 TF的交互激活域是必要和充分的。在依赖于PU.1的人类癌细胞中，单个氨基酸突变破坏PU.1-mSWI/SNF结合，损害复合物靶向，并减弱致癌转录和增殖。在分离中，SWIFT结构域的显性表达将TF从mSWI/SNF中分离出来，并毒害TF-“成瘾”的癌细胞。最后，跨不同家族的TFs与SMARCD平行特定的SWIFT域相互作用。这些结果确定了细胞类型和疾病特异性mSWI/SNF染色质靶向的主要机制，并为治疗调节方法提供了信息。
据了解，哺乳动物开关/蔗糖非发酵（mSWI/SNF）染色质重塑复合物调节DNA可及性和基因表达；然而，它们的基因组靶向机制仍不完全清楚。
附：英文原文
Title: A SWI/SNF-specific Ig-like domain, SWIFT, is a transcription factor binding platform
Author: 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. Sáme 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
Issue&Volume: 2026-04-02
Abstract: 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.
DOI: aeb3627
Source: https://www.science.org/doi/10.1126/science.aeb3627