A new insight into sex-specific non-coding RNAs and networks in response to SARS-CoV-2

Abstract

SARS-CoV-2 is the RNA virus responsible for COVID-19, the prognosis of which has been found to be slightly worse in men. The present study aimed to analyze the expression of different mRNAs and their regulatory molecules (miRNAs and lncRNAs) to consider the potential existence of sex-specific expression patterns and COVID-19 susceptibility using bioinformatics analysis. The binding sites of all human mature miRNA sequences on the SARS-CoV-2 genome nucleotide sequence were predicted by the miRanda tool. Sequencing data was excavated using the Galaxy web server from GSE157103, and the output of feature counts was analyzed using DEseq2 packages to obtain differentially expressed genes (DEGs). Gene set enrichment analysis (GSEA) and DEG annotation analyses were performed using the ToppGene and Metascape tools. Using the RNA Interactome Database, we predicted interactions between differentially expressed lncRNAs and differentially expressed mRNAs. Finally, their networks were constructed with top miRNAs. We identified 11 miRNAs with three to five binding sites on the SARS-COVID-2 genome reference. MiR-29c-3p, miR-21-3p, and miR-6838-5p occupied four binding sites, and miR-29a-3p had five binding sites on the SARS-CoV-2 genome. Moreover, miR-29a-3p, and miR-29c-3p were the top miRNAs targeting DEGs. The expression levels of miRNAs (125, 181b, 130a, 29a, b, c, 212, 181a, 133a) changed in males with COVID-19, in whom they regulated ACE2 expression and affected the immune response by affecting phagosomes, complement activation, and cell-matrix adhesion. Our results indicated that XIST lncRNA was up-regulated, and TTTY14, TTTY10, and ZFY-AS1 lncRN as were down-regulated in both ICU and non-ICU men with COVID-19. Dysregulation of noncoding-RNAs has critical effects on the pathophysiology of men with COVID-19, which is why they may be used as biomarkers and therapeutic agents. Overall, our results indicated that the miR-29 family target regulation patterns and might become promising biomarkers for severity and survival outcome in men with COVID-19.

Keywords: COVID-19; lncRNA; miR-29 family; microRNA.

Graphical abstract

Fig. 1

Schematic representation of human miRNA-binding sites on the SARS-CoV-2 genome.

Fig. 2

GSEA of all DEGs (up and down regulated) in response to SARS-COV-2 infection for COVID_female_ICU vs COVID_male_ICU (A), and COVID_female_NonICU vs COVID_male_NonICU (B).

Fig. 3

Networks were constructed between lncRNA-miRNA-mRNA for COVID_female_ICU vs COVID_male_ICU (A), and COVID_female_NonICU vs COVID_male_NonICU (B). Green hexagonal represents DElnRNAs, small yellow diamonds represent top miRNAs and light blue circles represent DEmRNAs respectively. We found TTY14 and LINC01505 as DElncRNAs which targeted PER1 (A). other DElncRNAs such as CLRN1-AS1 had interaction with both top miRNAs, but XIST targeted one miRNA (has-miR-29c-3p), in addition MAFA-AS1 targeted ID1. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)