Analysis and Validation of Autophagy-Related Gene Biomarkers and Immune Cell Infiltration Characteristic in Bronchopulmonary Dysplasia by Integrating Bioinformatics and Machine Learning.
Shuzhe Xiao, Yue Ding, Chen Du, Yiting Lv, Shumei Yang, Qi Zheng, Zhiqiu Wang, Qiaoli Zheng, Meifang Huang, Qingyan Xiao, Zhuxiao Ren, Guangliang Bi, Jie Yang
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引用次数: 0
Abstract
Background: Autophagy and immunity play important regulatory roles in lung developmental disorders. However, there is currently a lack of bioinformatics analysis on autophagy-related genes (ARGs) and immune infiltration in bronchopulmonary dysplasia (BPD). We aim to screen and validate the signature genes of BPD by bioinformatics and in vivo experiment.
Methods: GSE8586 was obtained from the Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified using the R program. Using cell-type identification with CIBERSORT to analyze the inflammatory and immune status of BPD. Subsequently, the hub genes were identified by Lasso and Cytoscape with three machine-learning algorithms (MCC, Degree and MCODE). In addition, hub genes were validated with ROC, single-cell sequence and IHC in hyperoxia rats. Finally, we searched the drug targets of these hub genes, and established a nomogram model for predicting the risk of BPD.
Results: There were 73 the differentially expressed and autophagy-related genes (DE-ARGs) by overlapping the DEGs in GSE8586 and ARGs. Five hub genes, BRIX1, JUN, PES1, NR4A1 and RRP9, were lowly expressed in the BPD group and had high diagnostic value in the diagnostic model. All hub genes are mainly located in B cell, epithelial cell, fibroblast, endothelial cell, smooth muscle cell and pneumocyte in lung single-cell sequencing. Moreover, immune infiltration analysis showed immune cells were higher in the BPD group and were closely associated with hub genes. We also predict the drug targets of the genes. Finally, the IHC result in rats showed that expression of PES1, BRX1, RRP9, JUN, NR4A1 was lower in the hyperoxia group compared to the normoxia group.
Conclusion: BRIX1, JUN, PES1, NR4A1, RRP9, may be promising therapeutic targets for BPD. Our findings provided researchers and clinicians with more evidence regarding immunotherapeutic strategies for BPD treatment.
背景：自噬和免疫在肺发育障碍中起着重要的调节作用。然而，目前缺乏自噬相关基因（ARGs）与支气管肺发育不良（BPD）免疫浸润的生物信息学分析。我们的目标是通过生物信息学和体内实验来筛选和验证BPD的特征基因。方法：从Gene Expression Omnibus （GEO）数据库中获取GSE8586。差异表达基因（DEGs）用R程序进行鉴定。利用CIBERSORT细胞类型鉴定分析BPD的炎症和免疫状态。随后，利用Lasso和Cytoscape三种机器学习算法（MCC、Degree和MCODE）鉴定中心基因。并用ROC、单细胞序列和IHC对高氧大鼠的hub基因进行验证。最后，我们搜索了这些枢纽基因的药物靶点，并建立了预测BPD风险的nomogram模型。结果：GSE8586和ARGs中存在73个差异表达和自噬相关基因（DE-ARGs）。5个枢纽基因BRIX1、JUN、PES1、NR4A1、RRP9在BPD组低表达，在诊断模型中具有较高的诊断价值。在肺单细胞测序中，所有枢纽基因主要位于B细胞、上皮细胞、成纤维细胞、内皮细胞、平滑肌细胞和肺细胞。免疫浸润分析显示BPD组免疫细胞增多，且与中枢基因密切相关。我们还预测了这些基因的药物靶点。最后，大鼠免疫组化结果显示，高氧组PES1、BRX1、RRP9、JUN、NR4A1的表达低于常氧组。结论：BRIX1、JUN、PES1、NR4A1、RRP9可能是BPD有前景的治疗靶点。我们的研究结果为研究人员和临床医生提供了更多关于BPD免疫治疗策略的证据。
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