Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis
Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by the production of autoantibodies, resulting in inflammation and organ damage. Although extensive research has been conducted on SLE pathogenesis, a comprehensive understanding of its molecular landscape in differen...
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Elsevier
2025-01-01
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| author | Blessy Kiruba Akshayata Naidu Vino Sundararajan Sajitha Lulu S |
| author_facet | Blessy Kiruba Akshayata Naidu Vino Sundararajan Sajitha Lulu S |
| author_sort | Blessy Kiruba |
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| description | Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by the production of autoantibodies, resulting in inflammation and organ damage. Although extensive research has been conducted on SLE pathogenesis, a comprehensive understanding of its molecular landscape in different cell types has not been achieved. This study uncovers the molecular mechanisms of the disease by thoroughly examining gene regulatory networks within neutrophils, dendritic cells, T cells, and B cells. Firstly, we identified genes and ncRNAs with differential expression in SLE patients compared to controls for different cell types. Furthermore, the derived differentially expressed genes were curated based on immune functions using functional enrichment analysis to create a protein-protein interaction network. Topological network analysis of the formed genes revealed key hub genes associated with each of the cell types. To understand the regulatory mechanism through which these hub genes function in the diseased state, their associations with transcription factors, and non-coding RNAs in different immune cell types were investigated through correlation analysis and regression models. Finally, by integrating these findings, distinct gene regulatory networks were constructed, which provide a novel perspective on the molecular, cellular, and immunological landscapes of SLE. Importantly, we reveal the crucial role of IRF3, IRF7, and STAT1 in neutrophils, dendritic cells, and T cells, where their aberrant upregulation in disease states might enhance the production of type I IFN. Furthermore, we found MYB to be a crucial regulator that might activate T cells toward autoimmune responses in SLE. Similarly, in B-cell lymphocytes, we found FOXO1 to be a key player in autophagy and chemokine regulation. These findings were also validated using single-cell RNASeq analysis using an independent dataset. Genotype variations of these genes were also explored using the GWAS central database to ensure their targetability. These findings indicate that IRF3, IRF7, STAT1, MYB, and FOXO1 are promising targets for therapeutic interventions for SLE. |
| format | Article |
| id | doaj-art-b51642d70c8349f892b6dc2301ce5f9c |
| institution | Kabale University |
| issn | 2405-8440 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Heliyon |
| spelling | doaj-art-b51642d70c8349f892b6dc2301ce5f9c2025-01-17T04:50:59ZengElsevierHeliyon2405-84402025-01-01111e41342Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysisBlessy Kiruba0Akshayata Naidu1Vino Sundararajan2Sajitha Lulu S3Department of Biosciences, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632 014, Tamil Nadu, IndiaDepartment of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632 014, Tamil Nadu, IndiaDepartment of Biosciences, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632 014, Tamil Nadu, IndiaDepartment of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore, 632 014, Tamil Nadu, India; Corresponding author. Department of Biotechnology School of Bio Sciences and Technology Vellore Institute of Technology Vellore, 632 014, Tamil Nadu, India.Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by the production of autoantibodies, resulting in inflammation and organ damage. Although extensive research has been conducted on SLE pathogenesis, a comprehensive understanding of its molecular landscape in different cell types has not been achieved. This study uncovers the molecular mechanisms of the disease by thoroughly examining gene regulatory networks within neutrophils, dendritic cells, T cells, and B cells. Firstly, we identified genes and ncRNAs with differential expression in SLE patients compared to controls for different cell types. Furthermore, the derived differentially expressed genes were curated based on immune functions using functional enrichment analysis to create a protein-protein interaction network. Topological network analysis of the formed genes revealed key hub genes associated with each of the cell types. To understand the regulatory mechanism through which these hub genes function in the diseased state, their associations with transcription factors, and non-coding RNAs in different immune cell types were investigated through correlation analysis and regression models. Finally, by integrating these findings, distinct gene regulatory networks were constructed, which provide a novel perspective on the molecular, cellular, and immunological landscapes of SLE. Importantly, we reveal the crucial role of IRF3, IRF7, and STAT1 in neutrophils, dendritic cells, and T cells, where their aberrant upregulation in disease states might enhance the production of type I IFN. Furthermore, we found MYB to be a crucial regulator that might activate T cells toward autoimmune responses in SLE. Similarly, in B-cell lymphocytes, we found FOXO1 to be a key player in autophagy and chemokine regulation. These findings were also validated using single-cell RNASeq analysis using an independent dataset. Genotype variations of these genes were also explored using the GWAS central database to ensure their targetability. These findings indicate that IRF3, IRF7, STAT1, MYB, and FOXO1 are promising targets for therapeutic interventions for SLE.http://www.sciencedirect.com/science/article/pii/S2405844024173732Systemic lupus erythematosusGene regulatory networksNon-coding RNAsInterferonsTargets |
| spellingShingle | Blessy Kiruba Akshayata Naidu Vino Sundararajan Sajitha Lulu S Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis Heliyon Systemic lupus erythematosus Gene regulatory networks Non-coding RNAs Interferons Targets |
| title | Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis |
| title_full | Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis |
| title_fullStr | Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis |
| title_full_unstemmed | Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis |
| title_short | Mapping integral cell-type-specific interferon-induced gene regulatory networks (GRNs) involved in systemic lupus erythematosus using systems and computational analysis |
| title_sort | mapping integral cell type specific interferon induced gene regulatory networks grns involved in systemic lupus erythematosus using systems and computational analysis |
| topic | Systemic lupus erythematosus Gene regulatory networks Non-coding RNAs Interferons Targets |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024173732 |
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