Gene fusion of IL7 involved in the regulation of idiopathic pulmonary fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a rare form of immune-mediated interstitial lung disease characterized by progressive pulmonary fibrosis and scarring. The pathogenesis of IPF is still unclear. Gene fusion events exist universally during transcription and show alternated patterns in a variety of lung diseases. Therefore, the comprehension of the function of gene fusion in IPF might shed light on IPF pathogenesis research and facilitate treatment development.

Methods: In this study, we included 91 transcriptome datasets from the National Center for Biotechnology Information (NCBI), including 52 IPF patients and 39 healthy controls. We detected fusion events in these datasets and probed gene fusion-associated differential gene expression and functional pathways. To obtain robust results, we corrected the batch bias across different projects.

Results: We identified 1550 gene fusion events in all transcriptomes and studied the possible impacts of IL7 = AC083837.1 gene fusion. The two genes locate adjacently in chromosome 8 and share the same promoters. Their fusion is associated with differential expression of 282 genes enriched in six Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and 35 functional gene sets. Gene ontology (GO) enrichment analysis shows that IL7 = AC083837.1 gene fusion is associated with the enrichment of 187 gene sets. The co-expression network of interleukin-7 (IL7) indicates that decreased IL7 expression is associated with many pathways that regulate IPF progress.

Conclusion: Based on the results, we conclude that IL7 = AC083837.1 gene fusion might exacerbate fibrosis in IPF via enhancing activities of natural killer cell-mediated cytotoxicity, skin cell apoptosis, and vessel angiogenesis, the interaction of which contributes to the development of fibrosis and the deterioration of respiratory function of IPF patients. Our work unveils the possible roles of gene fusion in regulating IPF and demonstrates that gene fusion investigation is a valid approach in probing immunologic mechanisms and searching potential therapeutic targets for treating IPF.The reviews of this paper are available via the supplemental material section.

Keywords: IL7; IPF; angiogenesis; apoptosis; fibrosis; fusion gene.

Figure 1.

Illustration of the locations of IL7 and AC083837.1 in chromosome 8 and their simultaneous transcription. Graphic created with Biorender.com. IL7, interleukin-7.

Figure 2.

Gene expression of the four genes directly associated with IL7 = AC083837.1 gene fusion. Bar values represent the mean ± SEM of the read counts of each gene, the p values were calculated by DESeq2. IL7, interleukin-7; IPF, idiopathic pulmonary fibrosis; SEM, standard error of the mean.

Figure 3.

Pearson correlation analysis of the expression of IL7 and AC083837.1. IL7, interleukin-7.

Figure 4.

Heatmap for the GO enrichment analysis. The heat map shows the clustered leading-edge genes in the gene sets. The x-axis represents the genes and y-axis represents gene sets. Red means positive correlation with IL7 = AC083837.1 gene fusion. GO, gene ontology; IL7, interleukin-7.

Figure 5.

Subset analysis of all enriched gene sets. The range of color stands for the overlap of the two gene sets.

Figure 6.

GO enrichment map associated with IL7 = AC083837.1 gene fusion. Node size stands for the GS size, edge width stands for the overlap size of the GS it connects, the color depth stands for the enrichment score (blue = negative, red = positive). Clusters: (1) GS associated with immune responses and tumor growth and regulation, (2) GS associated with reproduction, (3) GS associated with skin growth, (4) GS associated with extracellular matrix, (5) GS associated with IFN signaling pathways, (6) GS associated with immune cell growth, (7) GS of NK cell-mediated cytotoxicity, (8) GS associated with apoptosis and angiogenesis of endothelial and epithelial cells. GO, gene ontology; GS, gene set; IFN, interferon; IL7, interleukin-7; NK, natural killer.

Figure 7.

Co-expression network associated with expression of IL7. Node size stands for the GS size, edge width stands for the similarity coefficient of the GS it connects, the color depth stands for the enrichment score (blue = negative, red = positive). Clusters: (1) GS associated with reproduction, (2) GS associated with metabolism, (3) GS associated with extracellular matrix, (4) GS associated with vessel angiogenesis. GS, gene set; IL7, interleukin-7.

Figure 8.

The impacting pathways of IL7 = AC083837.1 gene fusion on the progression of IPF. The gene fusion enhances the expression of GS associate with apoptosis, angiogenesis, and NK cell-mediated cytotoxicity. These strengthened signaling pathways then exacerbate IPF symptoms through initiating and promoting the fibrosis process. The graphic was created with Biorender.com. GS, gene set; IL7, interleukin-7; IPF, idiopathic pulmonary fibrosis; NK, natural killer.