Single cell gene expression profiling of nasal ciliated cells reveals distinctive biological processes related to epigenetic mechanisms in patients with severe COVID-19

Objective: To explore the molecular processes associated with cellular regulatory programs in patients with COVID-19, including gene activation or repression mediated by epigenetic mechanisms. We hypothesized that a comprehensive gene expression profiling of nasopharyngeal epithelial cells might expand understanding of the pathogenic mechanisms of severe COVID-19. Methods: We used single-cell RNA sequencing (scRNAseq) profiling of ciliated cells (n = 12725) from healthy controls (SARS-CoV-2 negative n =13) and patients with mild/moderate (n =13) and severe (n =14) COVID-19. ScRNAseq data at the patient level were used to perform gene set and pathway enrichment analyses. We prioritized candidate miRNA-target interactions and epigenetic mechanisms. Results: Pathways linked to mitochondrial function, misfolded proteins, and membrane permeability were upregulated in patients with mild/moderate disease compared to healthy controls. Besides, we noted that compared to mild/moderate disease, cells derived from severe COVID-19 patients had downregulation of sub-networks associated with epigenetic mechanisms, including DNA and histone H3K4 methylation and chromatin remodeling regulation. We found 11-ranked miRNAs that may explain miRNA-dependent regulation of histone methylation, some of which share seed sequences with SARS-CoV-2 miRNAs. Conclusion: Our results may provide novel insights into the epigenetic mechanisms mediating the clinical course of SARS-CoV-2 infection.