用权重基因共表达网络分析识别心脏重构关键节点基因

摘要

Cardiac remodeling after acute myocardial infarction is the main pathologic change of chronic heart failure. The balance of ACEI and ACE2 plays an important role in pathogenesis and treatment of chronic heart failure. However its upstream regulation mechanism is unclear. This study aimed to identify the hub genes of cardiac remodeling by mining publically available data sets using weighted gene co-expression network analysis ( WGCNA ) and to study their relationship with ACEI and ACE2 gene. Methods Two genome-wide expression data sets, GSE7487 and GSE738 . of cardiac remodeling after myocardial infarction were downloaded from NCBI GEO database.WGCNA was used to construct gene coexpression network. identify the modules and hub genes associated with cardiac remodeling. The correlation of expression of hub genes with ACEI and ACE2 was calculated and verified in an animal model of cardiac remodeling after myocardial infarction. Result Seventeen modules were found in GSE7487 and among which, 6 were significantlv correlated with cardiac remodeling and enriched in 16 KEGG pathways. Sixteen modules were found in GSE738 and among which, 5 were significantly correlated with cardiac remodeling and enriched in 15 KEGG pathways, 10 of which were the same as in the first dataset. Many signaling pathways involved pathological cardiac hypertrophy , oxidative phosphorylation ,and metabolism. A number of key regulatory genes of cardiac remodeling were further identified through module connectivity and gene significance. One of the key regulatory genes, calcium-dependent phosphatase regulon ( RCANI ). was found to be highly correlated with ACEI, but not ACE2. Their relationships were confirmed in an animal model. Conclusions Weighted gene co-expression network analysis is a robust systematic biological tool and can be used to identify the key regulatory genes of cardiac remodeling efficiently.RCANI may play an important role in regulating the balance of ACE1-ACE2 in renin-angiotensin system.%目的 采用权重基因共表达网络分析方法(WGCNA)挖掘心肌梗死后心脏重构的关键节点基因,并研究其与ACE1和ACE2的关系.方法 从NCBI的GEO下载2个心肌梗死后心脏重构的全基因组表达数据GSE7487和GSE738;数据初处理后,用WGCNA构建基因共表达网络,识别与心脏重构相关的模块与关键节点基因,分析关键节点基因与ACE1和ACE2的关联性;并在心肌梗死后心脏重构大鼠模型中验证它们的关系.结果 分析发现在GSE7487,17个模块中有6个模块与心脏重构相关,模块基因富集于16条KEGG信号通路.在GSE738,5个模块与心脏重构相关,模块基因富集于15条KEGG信号通路,其中有10条信号通路与第一组数据结果相同,这些信号通路涉及心肌肥厚病理、氧化磷酸化、代谢等.进一步利用模块内连通性和基因重要性找到了一些心脏重构的关键调控基因,如钙依赖磷酸酶调节子(RCAN1).RCAN1表达与ACE1表达高度相关,但与ACE2不相关.在动物模型中验证结果与上述结果一致.结论 权重基因共表达网络分析方法是一个高效的系统生物学方法,应用本方法发现了心脏重构的关键节点基因,其中RCAN1可能影响ACE1-ACE2在肾素血管紧张素系统中的平衡.