Computational analysis of microRNA-mediated interactions in SARS-CoV-2 infection

Abstract

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression found in more than 200 diverse organisms. Although it is still not fully established if RNA viruses could generate miRNAs, there are examples of miRNA like sequences from RNA viruses with regulatory functions. In the case of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), there are several mechanisms that would make miRNAs impact the virus, like interfering with viral replication, translation and even modulating the host expression. In this study, we performed a machine learning based miRNA prediction analysis for the SARS-CoV-2 genome to identify miRNA-like hairpins and searched for potential miRNA-based interactions between the viral miRNAs and human genes and human miRNAs and viral genes. Overall, 950 hairpin structured sequences were extracted from the virus genome and based on the prediction results, 29 of them could be precursor miRNAs. Targeting analysis showed that 30 viral mature miRNA-like sequences could target 1,367 different human genes. PANTHER gene function analysis results indicated that viral derived miRNA candidates could target various human genes involved in crucial cellular processes including transcription, metabolism, defense system and several signaling pathways such as Wnt and EGFR signalings. Protein class-based grouping of targeted human genes showed that host transcription might be one of the main targets of the virus since 96 genes involved in transcriptional processes were potential targets of predicted viral miRNAs. For instance, basal transcription machinery elements including several components of human mediator complex (MED1, MED9, MED12L, MED19), basal transcription factors such as TAF4, TAF5, TAF7L and site-specific transcription factors such as STAT1 were found to be targeted. In addition, many known human miRNAs appeared to be able to target viral genes involved in viral life cycle such as S, M, N, E proteins and ORF1ab, ORF3a, ORF8, ORF7a and ORF10. Considering the fact that miRNA-based therapies have been paid attention, based on the findings of this study, comprehending mode of actions of miRNAs and their possible roles during SARS-CoV-2 infections could create new opportunities for the development and improvement of new therapeutics.

Identification of Novel SARS-CoV-2 Drug Targets by Host MicroRNAs and Transcription Factors Co-regulatory Interaction Network Analysis

“…In herpesvirus, viral factors block the transcription initiation process by inhibiting TAF4. Targeting transcription process by SARS-CoV-2 could help in preventing the assembling of RNA polymerase II on host genes ( Saçar Demirci and Adan, 2020 ). Genome-wide target predictions have previously shown that TFs are susceptible to regulation by miRNAs ( Enright et al, 2003 ).…”

Role of SARS-CoV-2 in Altering the RNA-Binding Protein and miRNA-Directed Post-Transcriptional Regulatory Networks in Humans

“…Human miRs have been associated with a variety of pathophysiological pathways and demonstrate differential expression during viral infections [ 93 , 94 ]. Recently, a few computational studies have shed light on the interplay between human miRs and SARS-CoV-2 target genes, indicating a crucial role in regulating the viral load in host cells [ 95 , 96 ]. However, a comprehensive understanding of the functional role of host miRs during SARS-CoV-2 infection has remained elusive until now.…”

“…However, a comprehensive understanding of the functional role of host miRs during SARS-CoV-2 infection has remained elusive until now. Recently, a machine learning-based study predicted that miRs could impact SARS-CoV-2 infection through several mechanisms, such as interfering with replication, translation, and by modulation of the host gene expression [ 95 ]. In this study, we used a computational approach to investigate the potential binding sites of human miRs in the SARS-CoV-2 genome using FIMO [ 82 ].…”

“…We identified 22 miRNAs that could potentially bind throughout the length of the SARS-CoV-2 viral genome ( Figure 5 A and Supplementary Table S5 ). Among the human miRs likely to be sequestered on the SARS-CoV-2 genome, miR-374a-3p has recently been predicted to target the SARS-CoV-2 gene; in particular, it has been shown to target the gene encoding the spike protein, which is essential for virus entry into the host cell [ 95 , 97 ]. In addition to targeting the spike protein-encoding genes, miR-374a-3p is also predicted to target the ORF1ab in the SARS-CoV-2 genome that encodes for the 5′viral replicase, based on the function similarity of SARS-CoV-2 coding genes with SARS-CoV [ 98 ].…”

COVID-19: fighting the invisible enemy with microRNAs

“…The izMiR (miRNA prediction software) and PANTHER, bioinformatics based classification systems, identified the possible mature viral and host cell miRNA candidates that could play a crucial role in SARS-CoV-2 infection [59]. According to this study, SARS-CoV-2 genes (Spike, Envelope, Membrane, Nucleocapsid, ORF1ab, ORF3a, ORF6, ORF8, ORF7a, and ORF10) were targeted by multiple human miRNAs ( Figure 3) and these miRNAs already have previously known roles in multiple viral diseases, to illustrate, ORF1ab and ORF3a, two SARS-CoV-2 viral genes, were shown to be targeted by hsa-miRNA 203b-3p which was reported to suppress viral replication in Influenza [60].…”