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Bioinformatic analysis for potential biological processes and key targets of heart failure-related stroke

心力衰竭相关脑卒中的潜在生物学过程和关键靶点的生物学分析

Abstract

This study aimed to uncover underlying mechanisms and promising intervention targets of heart failure (HF)-related stroke. HF-related dataset GSE42955 and stroke-related dataset GSE58294 were obtained from the Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was conducted to identify key modules and hub genes. Gene Ontology (GO) and pathway enrichment analyses were performed on genes in the key modules. Genes in HF- and stroke-related key modules were intersected to obtain common genes for HF-related stroke, which were further intersected with hub genes of stroke-related key modules to obtain key genes in HF-related stroke. Key genes were functionally annotated through GO in the Reactome and Cytoscape databases. Finally, key genes were validated in these two datasets and other datasets. HF- and stroke-related datasets each identified two key modules. Functional enrichment analysis indicated that protein ubiquitination, Wnt signaling, and exosomes were involved in both HF- and stroke-related key modules. Additionally, ten hub genes were identified in stroke-related key modules and 155 genes were identified as common genes in HF-related stroke. OTU deubiquitinase with linear linkage specificity (OTULIN) and nuclear factor interleukin 3-regulated (NFIL3) were determined to be the key genes in HF-related stroke. Through functional annotation, OTULIN was involved in protein ubiquitination and Wnt signaling, and NFIL3 was involved in DNA binding and transcription. Importantly, OTULIN and NFIL3 were also validated to be differentially expressed in all HF and stroke groups. Protein ubiquitination, Wnt signaling, and exosomes were involved in HF-related stroke. OTULIN and NFIL3 may play a key role in HF-related stroke through regulating these processes, and thus serve as promising intervention targets.

概要

目的

本研究通过加权基因共表达网络分析(Weighted gene co-expression network analysis, WGCNA)揭示心力衰竭(心衰)相关脑卒中的发病机制, 为临床防治心衰相关脑卒中提供关键靶点.

创新点

本研究基于网络的研究策略, 首次揭示了心衰相关脑卒中的潜在分子相互作用机制以及可能参与的生物学过程, 并筛选出其中的关键基因.

方法

我们从基因表达综合数据库(Gene Expression Omnibus database, GEO)中分别获得心衰和脑卒中相关的芯片数据, 并通过WGCNA鉴定各自的关键模块与关键基因. 然后我们将二者的关键模块与关键基因取交集后, 得到心衰相关脑卒中的关键基因, 并利用Reactome和Cytoscape数据库对关键基因进行功能注释. 最后在多个数据集中对心衰相关脑卒中的关键基因进行验证.

结果

我们在心衰和脑卒中相关芯片数据中分别鉴定出两个关键模块, 随后功能富集分析发现两种疾病的关键模块中的基因均参与了蛋白质泛素化, Wnt信号通路和外泌体三个生物学过程. 取交集后, 我们共得到155个共同基因, 他们可能参与了心衰相关脑卒中的发病机制. 其中, OTULINNFIL3被识别为心衰相关脑卒中的关键基因. 功能注释分析显示, OTULIN参与了蛋白质泛素化和Wnt信号通路, NFIL3参与了转录和翻译过程. 最后, 在多个心衰和脑卒中的芯片数据中均证实OTULINNFIL3表达显著上调.

结论

蛋白质泛素化, Wnt信号通路和外泌体等生物学过程在心衰相关脑卒中的发病机制中发挥了重要作用. OTULIN和NFIL3通过调节这些通路因而可作为心衰相关脑卒中潜在的干预靶点.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81900387), the Guangdong Basic and Applied Basic Research Fund (No. 2019A1515011806), the Fundamental Research Funds for the Central Universities (No. 19ykpy97), and the Science and Technology Program of Guangzhou City of China (No. 201803040010).

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Contributions

Zhaoyu LIU and Jingfeng WANG directed the project. Haifeng ZHANG designed experiments. Chiyu LIU and Sixu CHEN performed experiments and data analysis. Chiyu LIU drafted the manuscript. Yangxin CHEN, Qingyuan GAO, and Zhiteng CHEN perfected the manuscript. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.

Corresponding authors

Correspondence to Zhaoyu Liu or Jingfeng Wang.

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Chiyu LIU, Sixu CHEN, Haifeng ZHANG, Yangxin CHEN, Qingyuan GAO, Zhiteng CHEN, Zhaoyu LIU and Jingfeng WANG declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Liu, C., Chen, S., Zhang, H. et al. Bioinformatic analysis for potential biological processes and key targets of heart failure-related stroke. J. Zhejiang Univ. Sci. B 22, 718–732 (2021). https://doi.org/10.1631/jzus.B2000544

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Key words

  • Cardioembolic stroke
  • Heart failure
  • Bioinformatics
  • Weighted gene co-expression network analysis (WGCNA)

关键词

  • 心力衰竭
  • 心源性卒中
  • 生物信息学分析
  • 加权基因共表达网络分析(WGCNA)