Abstract
Background: Burn injury is a life-threatening disease that does not have ideal biomarkers. Therefore, this study first applied weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) screening methods to identify pivotal genes and diagnostic biomarkers associated with the skin burn process. Methods: After obtaining transcriptomic datasets of burn patient skin and normal skin from Gene Expression Omnibus (GEO) and performing differential analysis and functional enrichment, WGCNA was used to identify hub gene modules associated with burn skin processes in the burn patient peripheral blood sample dataset and determine the correlation between modules and clinical features. Enrichment analysis was performed to identify the functions and pathways of key module genes. Differential analysis, WGCNA, protein-protein interaction analysis, and enrichment analysis were utilized to screen for hub genes. Hub genes were validated in two other GEO datasets, tested by immunohistochemistry for hub gene expression in burn patients, and receiver operating characteristic curve analysis was performed. Finally, we constructed the specific drug activity, transcription factors, and microRNA regulatory network of the five hub genes. Results: A total of 1,373 DEGs in GSE8056 were obtained, and the top 5 upregulated genes were S100A12, CXCL8, CXCL5, MMP3, and MMP1, whereas the top 5 downregulated genes were SCGB1D2, SCGB2A2, DCD, TSPAN8, and KRT25. DEGs were significantly enriched in the immunity, epidermal development, and skin development processes. In WGCNA, the yellow module was identified as the most closely associated module with tissue damage during the burn process, and the five hub genes (ANXA3, MCEMP1, MMP9, S100A12, and TCN1) were identified as the key genes for burn injury status, which consistently showed high expression in burn patient blood samples in the GSE37069 and GSE13902 datasets. Furthermore, we verified using immunohistochemistry that these five novel hub genes were also significantly elevated in burn patient skin. In addition, MCEMP1, MMP9, and S100A12 showed perfect diagnostic performance in the receiver operating characteristic analysis. Conclusion: In conclusion, we analyzed the changes in genetic processes in the skin during burns and used them to identify five potential novel diagnostic markers in blood samples from burn patients, which are important for burn patient diagnosis. In particular, MCEMP1, MMP9, and S100A12 are three key blood biomarkers that can be used to identify skin damage in burn patients.
Highlights
Thermal injury is a challenging disease and a leading cause of death worldwide (Greenhalgh, 2019)
We extracted the top 100 differentially expressed genes (50 upregulated and 50 downregulated) as the most significant differentially expressed genes according to log2|fold change (FC)| size
We found that burn wound tissue-related genes with significant expression differences were mainly enriched in biological processes (BPs) such as immunity, epidermal development, and skin development, cellular components (CCs) such as collagen extracellular matrix (ECM), and molecular functions (MFs) such as signal transduction receptor activity
Summary
Thermal injury is a challenging disease and a leading cause of death worldwide (Greenhalgh, 2019). Clinical diagnosis by visual and tactile examination remains the current standard for determining the depth of a patient’s burn injury. This method has a serious lag in determining the patient’s condition and does not provide timely information regarding the patient’s progress due to the rapid progression of burn injury (Lee et al, 2020). We hypothesize that the extensive perturbations of the skin caused by thermal injury lead to differential changes in gene expression in peripheral blood tissues, which can be useful for diagnosing burns and identifying changes in burn conditions. This study first applied weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) screening methods to identify pivotal genes and diagnostic biomarkers associated with the skin burn process
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