Huanyi Zhao, Na Tang, Liang Xu, Junlong Li, Jianbin Pi* and Qingmin Chu* Pages 188 - 209 ( 22 )
Background: Recent studies have shown that dysfunction in chromatin regulators (CRs) may be an important mechanism of myocardial infarction (MI). They are thus expected to become a new target in the diagnosis and treatment of MI. However, the diagnostic value of CRs in MI and the mechanisms are not clear.
Methods: CRs-related differentially expressed genes (DEGs) were screened between healthy controls and patients with MI via GSE48060, GSE60993, and GSE66360 datasets. DEGs were further analyzed for enrichment analysis. Hub genes were screened by least absolute shrinkage and selection operator (LASSO) regression and weighted gene co-expression network analysis (WGCNA). GSE61144 datasets were further used to validate hub genes. RT-qPCR examined peripheral blood mononuclear cells (PBMCs) to verify expressions of hub genes. In addition, a correlation between hub genes and immune cell infiltration was identified by CIBERSORT and single-sample gene set enrichment analysis (ssGSEA). Finally, we constructed a diagnostic nomogram and ceRNA network and found possible therapeutic medicines which were based on hub genes.
Results: Firstly, 16 CR-related DEGs were identified. Next, Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and transcriptional regulator Jun dimerization protein 2 (JDP2) were selected as hub genes by LASSO and WGCNA. Receiver operating characteristic curves in the training and test data sets verified the reliability of hub genes. Results of RT-qPCR confirmed the upregulation of hub genes in MI. Subsequently, the immune infiltration analysis indicated that DUSP1, GADD45A, and JDP2 were correlated with plasmacytoid dendritic cells, natural killer cells, eosinophils, effector memory CD4 T cells, central memory CD4 T cells, activated dendritic cells, and activated CD8 T cells. Furthermore, a nomogram that included DUSP1, GADD45A, and JDP2 was created. The calibration curve, decision curve analysis, and the clinical impact curve indicated that the nomogram could predict the occurrence of MI with high efficacy. The results of the ceRNA network suggest that hub genes may be cross-regulated by various lncRNAs and miRNAs. In addition, 10 drugs, including 2H-1-benzopyran, Nifuroxazide, and Bepridil, were predicted to be potential therapeutic agents for MI.
Conclusion: Our study identifies three promising genes associated with the progression of chromatin regulators (CRs)-related myocardial infarction (MI) and immune cell infiltration, including Dual-specificity phosphatase 1 (DUSP1), growth arrest and DNA damage-inducible 45 (GADD45A), and Jun dimerization protein 2 (JDP2), which might be worthy of further study.
Myocardial infarction, chromatin regulators, immune cell infiltration, bioinformatics, peripheral blood mononuclear cells, dual-specificity phosphatase 1.