Gene Network Analysis of the Transcriptome Impact of SARS-CoV-2 Interacting MicroRNAs in COVID-19 Disease

Abstract

According to the World Health Organization (WHO), as of June 2022, over 536 million confirmed COVID-19 disease cases and over 6.3 million deaths had been globally reported. COVID-19 is a multiorgan disease involving multiple intricated pathological mechanisms translated into clinical, biochemical, and molecular changes, including microRNAs. MicroRNAs are essential post-transcriptional regulators of gene expression, being involved in the modulation of most biological processes. In this study, we characterized the biological impact of SARS-CoV-2 interacting microRNAs differentially expressed in COVID-19 disease by analyzing their impact on five distinct tissue transcriptomes. To this end, we identified the microRNAs' predicted targets within the list of differentially expressed genes (DEGs) in tissues affected by high loads of SARS-CoV-2 virus. Next, we submitted the tissue-specific lists of the predicted microRNA-targeted DEGs to gene network functional enrichment analysis. Our data show that the upregulated microRNAs control processes such as mitochondrial respiration and cytokine and cell surface receptor signaling pathways in the heart, lymph node, and kidneys. In contrast, downregulated microRNAs are primarily involved in processes related to the mitotic cell cycle in the heart, lung, and kidneys. Our study provides the first exploratory, systematic look into the biological impact of the microRNAs associated with COVID-19, providing a new perspective for understanding its multiorgan physiopathology.

Keywords: SARS-CoV-2; microRNA; network analysis.

Figure 1

The analytical pipeline used in the current study. N—number of research papers included in the analysis; n—number of microRNAs; arrow up—upregulated microRNAs; arrow down—downregulated microRNAs.

Figure 2

Cluster and functional enrichment analysis of COVID−19 heart DEGs targeted by differentially expressed microRNAs: STRING interaction confidence score > 0.7; Markov clustering inflation value = 4; STRING Enrichment FDR < 0.05; redundancy score = 0.5. (A) Cluster and functional enrichment analysis of COVID-19 heart downregulated DEGs targeted by upregulated microRNAs. (B) Cluster and functional enrichment analysis of COVID-19 heart upregulated DEGs targeted by downregulated microRNAs.

Figure 3

Cluster and functional enrichment analysis of COVID−19 lung upregulated DEGs targeted by downregulated microRNAs. STRING interaction confidence score > 0.7; Markov clustering inflation value = 4; STRING Enrichment FDR < 0.05; redundancy score = 0.5.

Figure 4

Cluster and functional enrichment analysis of COVID−19 lymph node downregulated DEGs targeted by upregulated microRNAs. STRING interaction confidence score > 0.7; Markov clustering inflation value = 4; STRING Enrichment FDR < 0.05; redundancy score = 0.5.

Figure 5

Cluster and functional enrichment analysis of COVID−19 kidneys DEGs targeted by differentially expressed microRNAs: STRING interaction confidence score > 0.7; Markov clustering inflation value = 4; STRING Enrichment FDR < 0.05; redundancy score = 0.5. (A) Cluster and functional enrichment analysis of COVID-19 kidney downregulated DEGs targeted by upregulated microRNAs. (B) Cluster and functional enrichment analysis of COVID-19 kidney upregulated DEGs targeted by downregulated microRNAs.

Figure 6

Cluster and functional enrichment analysis of COVID-19 liver DEGs targeted by differentially expressed microRNAs: STRING interaction confidence score > 0.7; Markov clustering inflation value = 4; STRING Enrichment FDR < 0.05; redundancy score = 0.5. (A) Cluster and functional enrichment analysis of COVID-19 liver downregulated DEGs targeted by upregulated microRNAs. (B) Cluster and functional enrichment analysis of COVID-19 liver upregulated DEGs targeted by downregulated microRNAs.

Figure 6

Cluster and functional enrichment analysis of COVID-19 liver DEGs targeted by differentially expressed microRNAs: STRING interaction confidence score > 0.7; Markov clustering inflation value = 4; STRING Enrichment FDR < 0.05; redundancy score = 0.5. (A) Cluster and functional enrichment analysis of COVID-19 liver downregulated DEGs targeted by upregulated microRNAs. (B) Cluster and functional enrichment analysis of COVID-19 liver upregulated DEGs targeted by downregulated microRNAs.