Given the critical role of chromatin factors such as topoisomerase I in regulating the transcriptional response to SARS-CoV-2 infection, Ho et al. evaluated transcriptional and epigenetic changes in the human alveolar basal epithelial carcinoma (A549) cell line expressing the human SARS-CoV-2 entry receptor Ace2 (A549-ACE2) infected with SARS-CoV-2 followed by the depletion of topoisomerase I and discovered promising effects of epigenetic therapy in modifying aberrant genome restructuring and selective suppression of inflammatory and anti-viral genes involved in severe COVID-19 [13]. Here, ACE2 is linked to COVID-19.