A chemically-targetable transcription factor-chromatin remodeler interaction underlies SARS-CoV-2 susceptibility

Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and provides novel therapeutic targets. Here, we demonstrate that the mSWI/SNF chromatin remodeling complex promotes coronavirus infection and represents a host-directed therapeutic target. SMARCA4 catalytic activity is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, which is essential for ACE2 expression and virus susceptibility. Recruitment of mSWI/SNF complexes to ACE2 is mediated by mSWI/SNF binding to the transcription factor, HNF1A, enabling complex occupancy and chromatin accessibility at sites containing high HNF1A motif density. Notably, small molecule inhibition of mSWI/SNF catalytic activity abrogates ACE2 expression confers resistance to SARS-CoV-2 variants and infection of primary human airway cells by 5-logs. These data highlight the role for mSWI/SNF-mediated chromatin remodeling activities in conferring SARS-CoV-2 susceptibility and identify a potential new class of inhibitors to combat COVID-19. Overall design: CUT&Tag, RNA-seq, and ATAC-seq in wild type and SMARCA4 KO Vero E6 cells to investigate the mechanism behind SARS-CoV-2 resistance after BAF inhibition