MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19

Manoj Khokhar; Sojit Tomo; Purvi Purohit

doi:10.1016/j.mgene.2021.100990

MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19

Meta Gene. 2022 Feb:31:100990. doi: 10.1016/j.mgene.2021.100990. Epub 2021 Oct 26.

Authors

Manoj Khokhar¹, Sojit Tomo¹, Purvi Purohit¹

Affiliation

¹ Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur 342005, India.

Abstract

Background: Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future.

Methods: The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape.

Results: Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors.

Conclusion: An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.

Keywords: AHR, Aryl hydrocarbon receptor; ARDS, acute respiratory distress syndrome; BAL, Bronchoalveolar Lavage; CC, Cellular components; CCL, Chemokine (C-C motif) ligands; CCL2, C-C motif chemokine 2; CCL3, C-C motif chemokine 3; CCL4, C-C motif chemokine 4; CCR, CC chemokine receptor; CEBPA, CCAAT/enhancer-binding protein alpha; COVID-19; COVID-19, Coronavirus Disease 2019; CREM, cAMP responsive element modulator; CRIEGs, Cytokine regulating immune expressed genes; CSF2, Granulocyte-macrophage colony-stimulating factor; CSF3, Granulocyte colony-stimulating factor; CXCL10, C-X-C motif chemokine 10; CXCL2, Chemokine (C-X-C motif) ligand 2; CXCL8, Interleukin-8; CXCR, C-X-C chemokine receptor; Cytokine storm; Cytokines; DDIT3, DNA damage-inducible transcript 3 protein; DEGs, Differentially expressed genes; E2F1, Transcription factor E2F1; EGR1, Early growth response protein 1; EP300, Histone acetyltransferase p300; ESR1, Estrogen receptor, Nuclear hormone receptor; ETS2, Protein C-ets-2; FOXP3, Forkhead box protein P3; GO, Gene Ontology; GSEs, Gene Series Expressions; HDAC1, Histone deacetylase 1; HDAC2, Histone deacetylase 2; HSF1, Heat shock factor protein 1; IL-6, interleukin-6; IL10, Interleukin-10; IL17A, Interleukin-17A; IL1B, Interleukin-1; IL2, Interleukin-2; IL6, Interleukin-6; IL7, Interleukin-7; IL9, Interleukin-9; IP-10, Interferon-Inducible Protein 10; IRF1, Interferon regulatory factor 1; Immuno-interactomics; JAK-STAT, Janus kinase (JAK)-signal transducer and activator; JAK2, Tyrosine-protein kinase JAK2; JUN, Transcription factor AP-1; KEGG, Kyoto Encyclopedia of Genes and Genomes; KLF4, Krueppel-like factor 4; MicroRNA, SARS-CoV-2; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFAT5, Nuclear factor of activated T-cells 5; NFKB1, Nuclear factor NF-kappa-B p105 subunit; NFKBIA, NF-kappa-B inhibitor alpha; NR1I2, Nuclear receptor subfamily 1 group I member 2; PDM, peripheral blood mononuclear cell; REL, Proto-oncogene c-Rel; RELA, Transcription factor p65; RUNX1, Runt-related transcription factor 1; SARS-CoV-2, Severe Acute Respiratory Syndrome Coronavirus 2; SIRT1, NAD-dependent protein deacetylase sirtuin-1; SP1, Transcription factor Sp1; SPI1, Transcription factor PU.1; STAT1, Signal transducer and activator of transcription 1-alpha/beta; STAT3, Signal transducer and activator of transcription 3; TLR3, Toll-like receptor 3 (TLR3); TNF, Tumor necrosis factor; TNF-α, Tumor Necrosis Factor-Alpha; VDR, Vitamin D3 receptor; XBP1, X-box-binding protein 1; ZFP36, mRNA decay activator protein ZFP36; ZNF300, Zinc finger protein 300, heme oxygenase-1 (HO-1); miEAA, miRNA Enrichment Analysis and Annotation t.