The accessible promoter-mediated supplementary effect of host factors provides new insight into the tropism of SARS-CoV-2.

In the past year, the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the worldwide coronavirus disease 2019 (COVID-19) pandemic. Yet our understanding of the SARS-CoV-2 tropism mechanism is still insufficient. In this study, we examined the chromatin accessibility at the promoters of host factor genes (, , , , , and ) in 14 tissue types, 23 tumor types, and 189 cell lines. We showed that the promoters of and were accessible in a tissue- and cell-specific pattern, which is accordant with previous clinical research on SARS-CoV-2 tropism. We were able to further verify that type I interferon (IFN) could induce angiotensin-converting enzyme 2 (ACE2) expression in Caco-2 cells by enhancing the binding of HNF1A, the transcription factor of ACE2, to ACE2 promoter without changing chromatin accessibility. We then performed transcription factor (TF)-gene interactions network and pathway analyses and discovered that the TFs regulating host factor genes are enriched in pathways associated with viral infection. Finally, we established a novel model that suggests that open chromatin at the promoter mediates the host factors' supplementary effect and ensures SARS-CoV-2 entry. Our work uncovers the relationship between epigenetic regulation and SARS-CoV-2 tropism and provides clues for further investigation of COVID-19 pathogenesis.