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

Mammalian SWI/SNF (BAF) chromatin remodeling complexes modulate DNA accessibility and gene expression, however, the mechanisms by which they 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 an evolutionarily conserved, broad transcription factor (TF) binding platform. SWIFT is necessary and sufficient for direct interaction with the transactivation domain of a lineage-specific TF, PU.1, in vitro and in cells, with a single amino acid mutation in SWIFT able to disrupt PU.1-mSWI/SNF binding, inhibit site-specific complex targeting and activity, and attenuate oncogenic gene expression and proliferation of PU.1-dependent cancer cells. Dominant expression of SWIFT in isolation across cell types sequesters mSWI/SNF-interacting TFs and poisons TF-addicted cancer cells. Finally, TFs interact with SWIFT in a SMARCD paralog-specific manner, informing approaches for modulation of cell type- and disease-specific transcription. Overall design: First, cells (hMSC, BIN-67, and U2OS) were transducted to express a given transcription factor, and ATAC-seq (in replicate) and chromatin profiling was performed. In another set of experiments, cells (hMSC, BIN-67, MOLM-13, and U-2 OS) were transducted to express both a given transcription factor and mSWI/SNF chromatin remodeling complex subunit either wild-type or mutated) and chromatin profiling, RNA-seq (in replicate), and ATAC-seq (in replicate) was again performed. Finally, transduction of the SMARCD2-SWIFT domain was performed in U-2 OS and CUT&RUN and ATAC-seq (in replicate) was performed.