Jain Siddhant U, Williamson Kaylyn E, Ying Alexander W, Jiang Ruidong Jerry, Turner Aasha M, So Kevin, Allison Maxwell P, Sankar Akshay, Sáme Guerra Daniel D, Mashtalir Nazar, Rohrs Henry W, Lichti Cheryl F, Gygi Steven P, Paulo Joao A, Gross Michael L, Kadoch Cigall
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
bioRxiv. 2025 Aug 1:2025.08.01.667725. doi: 10.1101/2025.08.01.667725.
Mammalian SWI/SNF (BAF) chromatin remodeling complexes modulate DNA accessibility and gene expression, however, the mechanisms by which these master regulatory complexes are targeted on chromatin remain incompletely understood. Here, we define SWIFT (SWI/SNF Ig-Fold for Transcription Factor Interactions) found on the SMARCD family of subunits within the core module as a transcription factor (TF) binding platform. We demonstrate that SWIFT is necessary and sufficient for direct interaction with the transactivation domain of a lineage-specific TF, PU.1, in vitro and in cells. A single amino acid mutation in SWIFT disrupts the PU.1-mSWI/SNF interaction, inhibits site-specific complex targeting and activity, and attenuates oncogenic gene expression and proliferation of PU.1-dependent AML cells. Dominant expression of SWIFT in isolation sequesters mSWI/SNF-interacting TFs and poisons TF-addicted cancer cells. Finally, we present SWIFT as an evolutionarily conserved domain that serves as a universal binding platform for diverse TFs, suggesting approaches for modulation of cell type and disease-specific transcription.
哺乳动物的SWI/SNF（BAF）染色质重塑复合物可调节DNA的可及性和基因表达，然而，这些主要调控复合物靶向染色质的机制仍未完全清楚。在这里，我们将核心模块内SMARCD亚基家族上发现的SWIFT（用于转录因子相互作用的SWI/SNF免疫球蛋白折叠）定义为转录因子（TF）结合平台。我们证明，SWIFT在体外和细胞内对于与谱系特异性TF即PU.1的反式激活结构域直接相互作用是必要且充分的。SWIFT中的单个氨基酸突变会破坏PU.1与mSWI/SNF的相互作用，抑制位点特异性复合物的靶向和活性，并减弱致癌基因的表达以及PU.1依赖性急性髓系白血病细胞的增殖。单独的SWIFT显性表达会隔离与mSWI/SNF相互作用的TF并毒害对TF成瘾的癌细胞。最后，我们提出SWIFT是一个进化上保守的结构域，可作为多种TF的通用结合平台，这为调节细胞类型和疾病特异性转录提供了方法。
