基于GEO数据库和生物信息学分析筛选小鼠心肌缺血再灌注损伤相关的潜在枢纽基因

doi:10.3969/j.issn.1674-8115.2022.01.008

上海交通大学学报(医学版) ›› 2022, Vol. 42 ›› Issue (1): 51-62.doi: 10.3969/j.issn.1674-8115.2022.01.008

基于GEO数据库和生物信息学分析筛选小鼠心肌缺血再灌注损伤相关的潜在枢纽基因

王建茹(), 彭广操, 朱明军()

河南中医药大学第一附属医院心内科，郑州 450099

收稿日期:2021-09-27 出版日期:2022-01-28 发布日期:2022-02-18
通讯作者: 朱明军 E-mail:wangjianru1988@126.com;zhumingjun317@163.com
作者简介:王建茹（1988—），男，主治医师，博士；电子信箱：wangjianru1988@126.com。
基金资助:
国家自然科学基金(82004311);河南省科技攻关项目(202102310492);河南省中医药科学研究专项课题(2019JDZX2013);河南省博士后科研项目(202001045);中原院士基金-中原名医

Screening potential hub genes associated with myocardial ischemia-reperfusion injury in mice based on GEO database and bioinformatics analysis

Jianru WANG(), Guangcao PENG, Mingjun ZHU()

Department of Cardiology, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450099, China

Received:2021-09-27 Online:2022-01-28 Published:2022-02-18
Contact: Mingjun ZHU E-mail:wangjianru1988@126.com;zhumingjun317@163.com
Supported by:
National Natural Science Foundation of China(82004311);Key Research and Development and Promotion Special Project of Henan Province (Scientific Problem Tackling) Project(202102310492);Traditional Chinese Medicine Scientific Research Special Project of Henan Province(2019JDZX2013);Postdoctoral Research Project of Henan Province(202001045);Zhongyuan Academician Foundation-Famous Doctor of Zhongyuan

摘要/Abstract

摘要：

目的·基于基因表达数据库（gene expression omnibus，GEO）运用生物信息学分析筛选与小鼠心肌缺血再灌注损伤（myocardium ischemia-reperfusion injury，MIRI）相关的潜在枢纽（hub）基因。方法·从GEO数据库中获取小鼠MIRI数据集GSE61592、GSE83472和GSE160516。利用limma包筛选各数据集中差异表达基因（differentially expressed genes，DEGs），再用稳健排序整合（robust rank aggregation，RRA）方法筛选稳健DEGs。构建稳健DEGs的蛋白质-蛋白质相互作用（protein-protein interaction，PPI）网络，并筛选PPI网络中的子模块和hub基因，利用clusterProfiler包对稳健DEGs、最重要子模块基因和hub基因进行基因本体论（gene ontology，GO）和京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）通路富集分析。将18只6~8周龄的C57BL/6 J雄性小鼠随机分为假手术（sham）组和MIRI组，每组9只，通过结扎冠状动脉左前降支，缺血30 min再灌注24 h，来构建MIRI模型。采用反转录-定量聚合酶链反应（reverse transcription-quantitative polymerase chain reaction，RT-qPCR）检测hub基因mRNA的表达情况。结果·RRA法在3个数据集中共鉴定出294个稳健DEGs。在PPI网络中，共筛选14个子模块，其中模块1最重要；共发现17个关键基因。GO和KEGG分析显示，稳健DEGs、模块1中的基因和hub基因主要涉及调控炎性细胞的迁移、趋化因子和细胞因子及其受体活性、Toll样受体等生物学功能和通路。RT-qPCR结果显示，与sham组相比，MIRI组小鼠心肌中趋化因子（C-C基序）配体4 ［chemokine （C-C motif） ligand 4，Ccl4］、Ccl6、Ccl7、趋化因子（C-X-C基序）受体4［chemokine （C-X-C motif） receptor 4，Cxcr4］、趋化因子（C-C基序）受体2 ［chemokine （C-C motif） receptor 2，Ccr2］、信号调节蛋白β1（signal-regulatory protein β 1，Sirpb1）、低亲和力免疫球蛋白γ Fc区受体Ⅱb（low affinity immunoglobulin gamma Fc region receptor Ⅱb，Fcgr2b）、白细胞表面抗原Cd53（leukocyte surface antigen CD53，Cd53）、花生四烯酸5-脂氧合酶激活蛋白（arachidonate 5-lipoxygenase activating protein，Alox5ap）、髓样分化初级反应基因88（myeloid differentiation primary response gene 88，Myd88）、巨噬细胞清道夫受体1（macrophage scavenger receptor 1，Msr1）、基质金属肽酶14（matrix metallopeptidase 14，Mmp14）、髓样细胞上表达的触发受体2（triggering receptor expressed on myeloid cells 2，Trem2）、桩蛋白（leupaxin，Lpxn）的mRNA表达上调，而低亲和力免疫球蛋白γ Fc区受体Ⅲ（low affinity immunoglobulin gamma Fc region receptor Ⅲ，Fcgr3）、补体C1q亚组分亚单位B（complement C1q subcomponent subunit B，C1qb）、去整合素和含金属蛋白酶结构域蛋白（a disintegrin and metalloproteinase domain-containing protein 8，Adam8）的mRNA表达未见差异。回顾文献，17个hub基因中Trem2、Lpxn、Cd53、Alox5ap、Sirpb1、Fcgr2b这6个基因未见报道参与MIRI。结论·该研究挖掘出小鼠MIRI相关的6个潜在hub基因，可为进一步探讨MIRI的分子机制和治疗靶点提供新的思路和切入点。

关键词: 心肌缺血再灌注损伤, 生物信息学分析, 差异表达基因, 关键基因, 基因表达数据库

Abstract:

Objective·To screen the potential hub genes associated with myocardial ischemia-reperfusion injury (MIRI) in mice by bioinformatics analysis based on gene expression omnibus (GEO) database.

Methods·The mouse MIRI data sets GSE61592, GSE83472 and GSE160516 were obtained from GEO database. The differentially expressed genes (DEGs) in each data set were screened by limma package, and then robust DEGs were screened by robust sorting integration (RRA) method. The protein-protein interaction (PPI) network of robust DEGs was constructed, and the submodules and hub genes in the PPI network were screened. The clusterProfiler package was used to analyze the robust DEGs, the most important submodule genes and hub genes by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Eighteen male C57BL/6 J mice aged 6?8 weeks were randomly divided into sham group and MIRI group, 9 mice each group. The MIRI model was constructed by left anterior descending coronary artery ligation for 30 min ischemia and 24 h reperfusion, and the mRNA expression of hub genes was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR).

Results·RRA method identified 294 robust DEGs in three data sets. In PPI network, a total of 14 sub-modules were screened, of which module 1 was the most important and 17 hub genes were found. GO and KEGG analysis showed that the robust DEGs, module 1 genes, and the hub genes were mainly involved in regulating the migration of inflammatory cells, the activity of chemokines and cytokines and their receptors, Toll-like receptors and other biological function and signaling pathways. RT-qPCR results showed that compared with the sham group, the expressions of chemokine (C-C motif) ligand 4 (Ccl4), Ccl6, Ccl7, chemokine (C-X-C motif) receptor 4 (Cxcr4), chemokine (C-C motif) receptor 2 (Ccr2), signal-regulatory protein β1 (Sirpb1), low affinity immunoglobulin gamma Fc region receptor Ⅱb (Fcgr2b), leukocyte surface antigen CD53 (Cd53), arachidonate 5-lipoxygenase activating protein (Alox5ap), myeloid differentiation primary response gene 88 (Myd88), macrophage scavenger receptor 1 (Msr1), matrix metallopeptidase 14 (Mmp14), triggering receptor expressed on myeloid cells 2 (Trem2) and leupaxin (Lpxn) were up-regulated in the myocardium of the MIRI group, but there was no difference inlow affinity immunoglobulin gamma Fc region receptor Ⅲ (Fcgr3), complement C1q subcomponent subunit B (C1qb) and a disintegrin and metalloproteinase domain-containing protein 8 (Adam8). By reviewing the literatures, Trem2, Lpxn, Cd53, Alox5ap, Sirpb1 and Fcgr2b were not reported to participate in MIRI.

Conclusion·This study has unearthed 6 potential hub genes for MIRI in mice, and the results can provide new ideas and entry points for further exploring the molecular mechanism and therapeutic targets of MIRI.

Key words: myocardium ischemia-reperfusion injury (MIRI), bioinformatics analysis, differentially expressed gene (DEG), hub gene, gene expression omnibus

中图分类号:

R541.4

王建茹, 彭广操, 朱明军. 基于GEO数据库和生物信息学分析筛选小鼠心肌缺血再灌注损伤相关的潜在枢纽基因[J]. 上海交通大学学报(医学版), 2022, 42(1): 51-62.

Jianru WANG, Guangcao PENG, Mingjun ZHU. Screening potential hub genes associated with myocardial ischemia-reperfusion injury in mice based on GEO database and bioinformatics analysis[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(1): 51-62.

图/表 9

图1 研究流程图

Fig 1 Flow chart of the study

表1 RT-qPCR引物序列

Tab 1 Primer sequences for RT-qPCR

Gene	Primer sequence	Gene	Primer sequence
β-actin	Forward 5'-CATCCGTAAAGACCTCTATGCCAAC-3'	C1qb	Forward 5'-CGTCGGCCCTAAGGGTACT-3'
	Reverse 5'-ATGGAGCCACCGATCCACA-3'		Reverse 5'-GGGGCTGTTGATGGTCCTC-3'
Fcgr3	Forward 5'-CAGAATGCACACTCTGGAAGC-3'	Myd88	Forward 5'-AGGACAAACGCCGGAACTTTT-3'
	Reverse 5'-GGGTCCCTTCGCACATCAG-3'		Reverse 5'-GCCGATAGTCTGTCTGTTCTAGT-3'
Fcgr2b	Forward 5'-ATGGGAATCCTGCCGTTCCTA-3'	Msr1	Forward 5'-AAGTATCAGCAGAAGTCCAGTCT-3'
	Reverse 5'-CCGTGAGAACACATGGACAGT-3'		Reverse 5'-TCCTTCAGTCTGAGGTCGTTG-3'
Ccl7	Forward 5'-GCTGCTTTCAGCATCCAAGTG-3'	Ccl4	Forward 5'-TTCCTGCTGTTTCTCTTACACCT-3'
	Reverse 5'-CCAGGGACACCGACTACTG-3'		Reverse 5'-CTGTCTGCCTCTTTTGGTCAG-3'
Adam8	Forward 5'-AGTTCCTGTTTATGCCCCAAAG-3'	Mmp14	Forward 5'-CAGTATGGCTACCTACCTCCAG-3'
	Reverse 5'-AAAGGTTGGCTTGACCTGCT-3'		Reverse 5'-GCCTTGCCTGTCACTTGTAAA-3'
Cxcr4	Forward 5'-GAAGTGGGGTCTGGAGACTAT-3'	Ccr2	Forward 5'-ATCCACGGCATACTATCAACATC-3'
	Reverse 5'-TTGCCGACTATGCCAGTCAAG-3'		Reverse 5'-CAAGGCTCACCATCATCGTAG-3'
Cd53	Forward 5'-AGCAGCCTGAAATTGCTGAAA-3'	Lpxn	Forward 5'-AGACCTTGTCATCGCAGGGTA-3'
	Reverse 5'-GGACCAGGAAATAGATGCCAAAG-3'		Reverse 5'-CAGGACTGATTCCTTTGGCTC-3'
Alox5ap	Forward 5'-AGCATGAAAGCAAGGCGCATA-3'	Trem2	Forward 5'-CTGGAACCGTCACCATCACTC-3'
	Reverse 5'-GTACGCATCTACGCAGTTCTG-3'		Reverse 5'-CGAAACTCGATGACTCCTCGG-3'
Ccl6	Forward 5'-GCTGGCCTCATACAAGAAATGG-3'	Sirpb1	Forward 5'-ACCATGTCTGAACTGAAAACGG-3'
	Reverse 5'-GCTTAGGCACCTCTGAACTCTC-3'		Reverse 5'-ACGCATGTAAATGACAGTGGC-3'

图2 各数据集的火山图Note： A. GSE61592. B. GSE83472. C. GSE160516. Red nodes represent up-regulated genes. Green nodes represent down-regulated genes. Black nodes represent genes with no significant expression differences.

Fig 2 Volcano plots for each data set

图3 前20个上调和下调稳健DEGs的热图Note： Red represents up-regulated robust DEGs. Green represents down-regulated robust DEGs. The values in the boxes are the log2FC values for robust DEGs.

Fig 3 Heat map of the top 20 up- and down-regulated robust DEGs

图4 稳健DEGs的功能富集分析Note：A. A bubble plot of the top 10 entries of the GO enrichment analysis for robust DEGs. The size of the bubble represents the number of targets for the entry and the bubble colour indicates enrichment significance. B. Circle diagram of KEGG pathway enrichment analysis of robust DEGs.

Fig 4 Functional enrichment analysis of robust DEGs

图5 稳健DEGs的PPI网络构建和模块分析Note： A. PPI network diagram for robust DEGs. B. PPI network of Module 1. Red represents upregulated genes and green represents downregulated genes. C. Bubble diagram for GO enrichment analysis of robust DEGs in Module 1. D. Bubble diagram of KEGG pathway enrichment analysis of robust DEGs in Module 1. The size of the bubble represents the number of targets for the entry and the colour of the bubble represents the significance of the enrichment.

Fig 5 PPI network construction and modular analysis of robust DEGs

图6 Hub基因的筛选及其功能富集分析Note： A. Upset map of the top 100 genes. MCC—maximal clique centrality; DMNC—density of maximum neighborhood component; MNC—maximum neighborhood component; EPC—edge percolated component. B. Network diagram of hub genes. C. Bubble diagram for GO enrichment analysis of hub genes. D. Bubble map of KEGG pathway enrichment analysis of hub gene.

Fig 6 Screening of hub genes and analysis of their functional enrichment

表2 Hub基因的相关信息

Tab 2 Information about the hub genes

Gene name	Log₂FC	Gene name	Log₂FC	P value
Fcgr3	2.162	C1qb	1.253	0.000
Ccl7	1.984	Myd88	1.246	0.000
Sirpb1	1.951	Msr1	1.179	0.009
Fcgr2b	1.437	Ccl4	1.151	0.000
Adam8	1.432	Mmp14	1.140	0.000
Cxcr4	1.407	Ccr2	1.091	0.011
Cd53	1.351	Trem2	1.069	0.002
Alox5ap	1.337	Lpxn	1.020	0.001
Ccl6	1.292

图7 Hub基因的验证Note： A. TTC staining of myocardial tissue in mice. The black dashed area is the infarcted tissue. The green dashed area is the magnification of some infarcted tissues. B. The mRNA expression of hub genes in the MIRI group and the sham group (n=3). ①P=0.000, ②P=0.002, compared with the sham group.

Fig 7 Validation of the hub genes

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基于GEO数据库和生物信息学分析筛选小鼠心肌缺血再灌注损伤相关的潜在枢纽基因

Screening potential hub genes associated with myocardial ischemia-reperfusion injury in mice based on GEO database and bioinformatics analysis

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