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

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 ( SW I/SNF I g-Fold for T ranscription F actor Interactions), found on the SMARCD family of subunits within the mSWI/SNF core module as an evolutionarily conserved, universal 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 acute myeloid leukemia (AML) cancer cells. Further, dominant expression of the SWIFT domain in isolation sequesters TFs from mSWI/SNF complexes and “poisons” TF-addicted cancer cells across different lineages. Finally, we uncover striking preferences of lineage-specific TFs for the SWIFT domains of specific SMARCD subunit paralogs. These SMARCD paralog-specific affinities of TFs align with their tissue- and differentiation state-specific expression patterns across human cells and tissues, suggesting that that switches in mSWI/SNF subunit composition fine-tune affinities for TFs that govern specialized cell state transitions during normal differentiation and tumorigenesis.In conclusion, this work unmasks a novel mSWI/SNF biochemical interface amenable to targeted therapeutic modulation in a diverse collection of transcriptionally addicted cancers.