Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect all organs in the body. It is characterized by hyperactivation of the immune system, resulting in abnormal production of autoantibodies, particularly antinuclear antibodies [
High-throughput sequencing is a new omics technology that has opened up a new frontier in disease genomics [
GSE46907 gene expression profile for peripheral blood monocytes both from SLE patients and controls was downloaded from the Gene Expression Omnibus database (available at
DEGs between SLE patients and controls were identified using the LIMMA package downloaded from Bioconductor (
GO (Gene Ontology) terms [
The STRING online database (
This study is aimed at identifying DEGs between normal and individuals with SLE. Given that exposure to anti-SLE drugs can interfere normal transcription, the selected SLE patients in GSE46907 were healthy, newly diagnosed with the disease, and naive for autoimmune medications. The expressed transcripts in SLE peripheral blood monocytes were obtained and analyzed. Compared with healthy control, a total of 134 DEGs were identified in individuals with SLE, in which 29 were downregulated, whereas 105 were upregulated. The heat map and volcano plot for the DEGs are shown in Figures
Heat map of hierarchical clustering analysis for the DEGs between SLE and healthy controls. Each row represents a gene, and each column represents a sample. Color indicates the level of gene expression. Red represents high expression, and green represents low expression. The top is the sample cluster tree, and the left is the gene cluster tree.
The volcano plots of genes in SLE and healthy control. The vertical lines represent |log2.0 fold change| of SLE/healthy control up and down, respectively, and the horizontal line represents adj.
Signaling pathway enrichment analysis of DEGs was performed using Metascape. The top 20 clusters for enriched sets are shown in Figure
Top 20 enriched terms of function enrichment analysis of the DEGs identified in SLE, analyzed by Metascape.
Pathway enrichment analysis of SLE-associated DEGs using Metascape.
Pathway enrichment analysis | Genes |
---|---|
R-HSA-913531: interferon signaling | HSPB1, RSAD2, OAS2, OASL, IFIT1, HERC5, OAS3, IFIT3, ISG15, IFI27, IFI44L, IFITM1, MX2, USP18, IFI44, CUL1, RTP4, IFI6, IFI35, MX1, EIF2AK2, IFIH1, LTF, XAF1, IFITM2, DDX60, IFIT5, IFIT2, TRIM22, CHMP5, PLSCR1, IFITM3, PSMB9, LHFPL2, UBE2L6, TRIM34, IRF7, ZBP1, BST2, IL1RN, RNASE2, STAT1, FCGR1B, IFI16, DEFA1, TRIM21, DDX58, CCL2, CCR5, STAP1, OPTN, CXCL10, ADAR, PLAC8, FOXO1, LGALS9, FCGR1A, CIITA, GBP1 |
GO:0034341: response to interferon-gamma | RSAD2, OAS2, OASL, IFIT1, OAS3, IFITM1, CUL1, MX1, EIF2AK2, IFIH1, TAP1, IFITM2, TRIM22, IFITM3, TRIM34, IRF7, BST2, STAT1, FCGR1B, TNFSF10, IFI16, TRIM21, DDX58, CCL2, GCH1, CXCL10, ADAR, LGALS9, FCGR1A, CIITA, GBP1 |
R-HSA-1169410: Antiviral mechanism by IFN-stimulated genes | RSAD2, OAS2, OASL, IFIT1, HERC5, AS3, ISG15, MX2, USP18, MX1, EIF2AK2, IFIH1, LTF, DDX60, GPR18, UBE2L6, IRF7, BST2, STAT1, DDX58, ANXA4, OPTN, LGALS9, GBP1 |
GO:0035455: response to interferon-alpha | IFIT1, IFIT3, IFITM1, MX2, EIF2, AK2, XAF1, IFITM2, IFIT2, PLSCR1, IFITM3, BST2, STAT1, IFI16, DEFA1, TRIM21, CCR5, ADAR, LGALS9 |
GO:0001817: regulation of cytokine product | HSPB1, RSAD2, HERC5, ISG15, EIF2AK2, IFIH1, LTF, DDX60, SORL1, GPR18, UBE2L6, IRF7, ZBP1, BST2, STAT1, IFI16, TRIM21, DDX58, IGF2BP3, ANXA4, LGALS9, GBP1 |
GO:0045088: regulation of innate immune response | RSAD2, USP18, CUL1, IFIH1, LTF, DDX60, LSCR1, PSMB9, IRF7, ZBP1, STAT1, FCGR1B, IFI16, DDX58, CTSL, STAP1, OPTN, ADAR, LGALS9, FCGR1A, GBP1, CD38 |
GO:0098586: cellular response to virus | HSPB1, RSAD2, NR2F6, IFIT1, ISG15, IFI27, IFI6, IFIH1, LTF, DDX60, SORL1, GPR18, IPO5, IRF7, ZBP1, IL1RN, STAT1, DEFA1, DDX58, CCL2, CCR5, ANXA4, CXCL10, ADAR, FOXO1, LGALS9, NR1D2, GBP1, CD38 |
GO:0060759: regulation of response to cytokine stimulus | SP18, IFIH1, IRF7, ZBP1, IL1RN, STAT1, DDX58, STAP1, CXCL10, ADAR |
GO:0009617: response to bacterium | HSPB1, NR2F6, OAS2, ISG15, IFITM1, IFI44, LTF, DDX60, CHMP5, HERC6, GPR18, RHOB, BST2, IL1RN, RNASE2, IFI16, PID1, DEFA1, TRIM21, CCL2, CCR5, STAP1, GCH1, OPTN, CXCL10, ADAR, PLAC8, FOXO1, LGALS9, NR1D2 |
GO:0043122: regulation of I-kappaB kinase/NF-kappaB signaling | HSPB1, EIF2AK2, LTF, ARID5B, IFIT5, TRIM22, GPR18, TRIM34, BST2, STAT1, TNFSF10, RIM21, DDX58, ANXA4, OPTN, LGALS9 |
R-HSA-983169: class I MHC-mediated antigen processing and presentation | HERC5, IFI27, SIGLEC1, IFITM1, CUL1, RASGRP3, TAP1, PLSCR1, PSMB9, HERC6, UBE2L6, FCGR1B, TRIM21, CTSL, STAP1, ATP6V0C, FCGR1A, GBP1, CD38 |
GO:0071888: macrophage apoptotic process | IRF7, CTSL, CCR5, LGALS9 |
GO:0043902: positive regulation of multiorganism process | IFIT1, DDX60, LHFPL2, TRIM21, OPTN, ADAR, LGALS9 |
GO:0070555: response to interleukin-1 | UL1, RASGRP3, PSMB9, IL1RN, STAT1, PID1, CCL2, CCR5, GCH1, CXCL10, FOXO1, H2AC18, H2AC19, LGALS9, GBP1, CD38 |
GO:0031400: negative regulation of protein modification process | HSPB1, IFIT1, ISG15, IFIH1, SORL1, CHMP5, IPO5, SKI, PRR7, STAT1, TNFSF10, PID1, TRIM21, DDX58, STAP1, ATP6V0C, ADAR, FOXO1, CRTAP, GBP1 |
GO:0061025: membrane fusion | MX2, MX1, TAP1, SAMD9, CCR5, OTOF |
R-HSA-977225: amyloid fiber formation | USP18, IFIH1, LTF, SORL1, PSMB9, UBE2L6, TRIM21, DDX58, UNG, H2AC18, H2AC19, FCGR1A |
GO:2000116: regulation of cysteine-type endopeptidase activity | HSPB1, ISG15, IFI27, CUL1, IFI6, LTF, SORL1, PSMB9, IRF7, PRR7, BST2, STAT1, TNFSF10, IFI16, ADAR, PABPC4, LGALS9, CD38 |
GO:0045055: regulated exocytosis | LGALS3BP, IFI27, EIF2AK2, ADGRE3, LTF, PLSCR1, LHFPL2, BST2, RNASE2, DEFA1, DDX58, ENPP4, OTOF, STAP1, UNG, ATP6V0C, OPTN, CXCL10, PLAC8, LGALS9, SCCPDH |
GO:0001881: receptor recycling | MX2, MX1, SORL1, CHMP5, OPTN |
A PPI network for the DEGs was constructed on the STRING website. The results were then visualized using Cytoscape (Figure
Protein-protein interaction (PPI) network of DEGs constructed using the STRING online database and Cytoscape 3.7.2, with 90 nodes and 973 edges. Red represents upregulated genes, while green represents downregulated genes.
Top 10 hub genes and cointeraction in the PPI network, constructed by cytoHubba of Cytoscape based on a degree score. Color scale represents highly of degree scores.
Top 10 hub genes with high degree of DEGs in SLE.
Gene symbol | Full name | Function | Degree |
---|---|---|---|
STAT1 | Signal transducer and activator of transcription | Signal transducer and transcription activator that mediates cellular responses to interferons (IFNs), cytokine KITLG/SCF, and other cytokines and other growth factors. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity and protein homodimerization activity. | 54 |
IRF7 | Interferon regulatory factor | Key transcriptional regulator of type I interferon- (IFN-) dependent immune responses and plays a critical role in the innate immune response against DNA and RNA viruses. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription factor activity. | 50 |
MX1 | MX dynamin-like GTPase 1 | Interferon-induced dynamin-like GTPase with antiviral activity against a wide range of RNA viruses and some DNA viruses. Gene Ontology (GO) annotations related to this gene include GTP binding and GTPase activity. | 49 |
OASL | 2 | Does not have 2 | 49 |
ISG15 | ISG15 ubiquitin-like modifier | Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. Gene Ontology (GO) annotations related to this gene include protein tag. | 48 |
IFIT3 | Interferon-induced protein with tetratricopeptide repeats 3 | IFN-induced antiviral protein which acts as an inhibitor of cellular as well as viral processes, cell migration, proliferation, signaling, and viral replication. Gene Ontology (GO) annotations related to this gene include identical protein binding. | 47 |
IFIH1 | Interferon induced with helicase C domain 1 | Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines. Gene Ontology (GO) annotations related to this gene include nucleic acid binding and hydrolase activity. | 47 |
IFIT1 | Interferon-induced protein with tetratricopeptide repeats 1 | Interferon-induced antiviral RNA-binding protein that specifically binds single-stranded RNA bearing a 5 | 46 |
OAS2 | 2 | Interferon-induced, dsRNA-activated antiviral enzyme which plays a critical role in cellular innate antiviral response. Gene Ontology (GO) annotations related to this gene include RNA binding and transferase activity. | 46 |
GBP1 | Guanylate binding protein 1 | Hydrolyzes GTP to GMP in 2 consecutive cleavage reactions. Exhibits antiviral activity against influenza virus. Promotes oxidative killing and delivers antimicrobial peptides to autophagolysosomes, providing broad host protection against different pathogen classes. Gene Ontology (GO) annotations related to this gene include identical protein binding and enzyme binding. | 46 |
SLE is a heterogeneous autoimmunity disease characterized by overexpression of antibodies against autoantigens [
Previous bioinformatics analysis showed that IFN signature and IFN signaling pathways against viral infections were strongly associated with the pathogenesis and development of SLE. High levels of serum IFN together with overexpression of IFN-inducible genes have been found in individuals with SLE. The level of IFN correlated with the severity of the disease [
Remarkably, our findings underscored the importance of IFN-
In conclusion, this study strengthens the critical role played by IFN signatures and IFN signaling pathway in SLE. Different from previous bioinformatics analyses, we analyzed the transcription profile of treatment of the naive SLE patients. We found that IFN-
The data used for analysis in this study are available from the Gene Expression Omnibus database freely.
The authors declare that there is no conflict of interest regarding the publication of this article.
We gratefully thank many researchers for providing technical assistance and all the patients who were enrolled in the study.
Supplementary Materials of Table 1: the results of differentially expressed genes (DEGs) of healthy and newly diagnosed SLE population.