The miRNA-gene regulatory circuits in nSARS-CoV-2 and their potential correlations with pulmonary and thrombotic disorders

Abstract

In view of the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection pandemic situation, research to repurpose drugs, identify novel drug targets, vaccine candidates, diagnostic markers etc have created a new race to curb the disease. To uncover nSARS-CoV-2-related important biological features and understanding the molecular basis of this disease, network biology and miRNA-gene regulatory motif-based approach is used. 11 antiviral human-microRNAs (miRNAs) which can potentially target SARS-CoV-2 genes were collated; their direct miRNA interactors were identified and a comprehensive nSARS-CoV-2 responsive miRNA:Transcription Factor (TF):gene coregulatory network was built. 1385 miRNA:TF:gene tripartite, Feed-Forward Loops (FFLs) were identified from the network. The network topology was mapped into the biological space and the overrepresented pathways were identified. Four regulatory circuits: hsa-mir-9-5p-EP300-PLCB4, hsa-mir-324-3p-MYC-HLA-F, hsa-mir-1827-E2F1-CTSV and hsa-mir-1277-5p-SP1-CANX are identified. These miRNA-gene regulatory circuits are found to regulate signalling pathways like virus endocytosis, viral replication, inflammatory response, pulmonary vascularization, cell cycle control, virus spike protein stabilization, antigen presentation, etc. Some novel computational evidences for understanding nSARS-CoV-2 molecular mechanisms controlled by these regulatory circuits is put forth. The novel associations of miRNAs and genes identified with this infection are open for experimental validation. Further, these regulatory circuits also suggest potential correlations/similarity in the molecular mechanisms during nSARS-CoV-2 infection and pulmonary diseases and thromboembolic disorders. A detailed molecular snapshot of TGF-β signalling pathway as the common mechanism that could play an important role in controlling common pathophysiology i.e. systemic inflammation, increased pulmonary pressure, ground glass opacities, D-dimer overexpression is also put forth.