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. 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

鉴定冠状病毒感染的宿主决定因子，可为解析病毒致病机制提供关键依据，并为开发新型治疗靶点提供方向。本研究证实，mSWI/SNF染色质重塑复合物可促进冠状病毒感染，可作为宿主靶向治疗的潜在靶点。SMARCA4的催化活性是mSWI/SNF介导的血管紧张素转换酶2（ACE2）位点染色质开放所必需的，而该染色质开放状态对于ACE2表达与病毒易感性至关重要。mSWI/SNF复合物向ACE2位点的招募，依赖于其与转录因子HNF1A的结合，从而使复合物能够在HNF1A基序密度较高的区域实现染色质占据与开放。值得注意的是，小分子抑制mSWI/SNF的催化活性可阻断ACE2表达，使细胞能够抵抗SARS-CoV-2变体感染，同时可将原代人呼吸道细胞的病毒感染滴度降低5个对数级。本研究数据阐明了mSWI/SNF介导的染色质重塑在调控SARS-CoV-2易感性中的关键作用，并鉴定出一类潜在的新型抗新型冠状病毒肺炎（COVID-19）抑制剂。本研究在野生型与SMARCA4敲除（KO）的Vero E6细胞中开展CUT&Tag技术、RNA测序（RNA-seq）与转座酶可及性测序（ATAC-seq）实验，以探究BAF抑制后SARS-CoV-2感染抗性的分子机制。