To explore the regulatory relationship between the 5 key genes, 3 coronavirus-related genes (ACE2, TMPRSS2, BSG), and their target miRNA, we used 6 miRNA target prediction databases to predict the target miRNA of these genes.
The proposed relationship was substantiated by an actual validation of seed complementarity, confirming the interaction between miR-98-5p and TMPRSS2 3'UTR both in HMVEC-L (Figure 2A) and HUVEC (Figure 2B) through a luciferase assay.
Hence, the potential role of these gender-associated miRNAs in immunity regulation and in modulation of viral receptors and co-receptors should be considered as a crucial factor in the observed different pathogenicity and lethality of COVID-19 in men and women (see Table 1).
Considering the significance of ACE2 and TMPRSS2 in SARS-CoV-2 infection, we also performed a TargetScan (http://www.targetscan.org/vert_72/) search for the miRNAs that could target these two receptors, and the analysis revealed a list of miRNAs such as, hsa-miRNA 200b-3p, hsa-miRNA 200c-3p and miRNA 429 for ACE2, and hsa-let 7c-5p, hsa-miRNA 98-5p, hsa-let 7f-5p, hsa-let 7a-5p, hsa-let 7g-5p, hsa-let 7b-5p, hsa-miRNA 4458, hsa-let 7e-5p, hsa-let 7i-5p, hsa-let 7d-5p, and hsa-miRNA 4500 for TMPRSS2.