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Identification of circulating hub long noncoding RNAs associated with hypertrophic cardiomyopathy using weighted correlation network analysis.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is one of the most commonly inherited heart diseases and the leading cause of sudden cardiac death among adolescents and young adults. Circulating long noncoding RNAs (lncRNAs) have demonstrated potential as diagnostic and therapeutic targets in several cardiovascular diseases. However, the circulating extracellular lncRNA expression profile of patients with HCM remains unclear. Plasma lncRNA expression was evaluated in patients with HCM and healthy controls using a human lncRNA microarray. A weighted correlation network analysis (WGCNA) and linear models for microarray data (Limma) were used. GSE68316 data from cardiac tissue in the Gene Expression Omnibus database were analysed for further validation. Using WGCNA, two modules (referred to as the magenta and the light?yellow module) were identified that were positively associated with HCM. Gene Ontology analysis revealed that lncRNAs in the magenta module targeted 'heart growth'. Using Limma, a total of 290 lncRNAs were differentially expressed (210 upregulated and 80 downregulated) in the plasma of HCM patients, compared with controls. Moreover, combined WGCNA and Limma analysis demonstrated that 27 hub lncRNAs in the magenta module and 13 hub lncRNAs in the light?yellow module were significantly upregulated, compared with the controls. Moreover, of the 40 differentially expressed hub lncRNAs identified in the two modules, three circulating lncRNAs (lnc?P2RY6?1:1, ENST00000488040 and ENST00000588047) were also significantly upregulated in the HCM cardiac tissue validation dataset. These lncRNAs may serve as biomarkers and therapeutic targets for precise diagnosis and treatment of HCM.

SUBMITTER: Guo Q

PROVIDER: S-EPMC7646839 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Identification of circulating hub long noncoding RNAs associated with hypertrophic cardiomyopathy using weighted correlation network analysis.

Guo Qi Q Wang Junjie J Sun Runlu R Gu Wenli W He Zhijian Z Chen Qian Q Liu Wenhao W Chen Yangxin Y Wang Jingfeng J Zhang Yuling Y

Molecular medicine reports 20201006 6

Hypertrophic cardiomyopathy (HCM) is one of the most commonly inherited heart diseases and the leading cause of sudden cardiac death among adolescents and young adults. Circulating long noncoding RNAs (lncRNAs) have demonstrated potential as diagnostic and therapeutic targets in several cardiovascular diseases. However, the circulating extracellular lncRNA expression profile of patients with HCM remains unclear. Plasma lncRNA expression was evaluated in patients with HCM and healthy controls usi ...[more]

PMID: 33174017

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Project description:BackgroundConsidering it is one of the major causes of sudden cardiac arrest, the proper management of hypertrophic cardiomyopathy (HCM) is essential. However, efficient treatment options for this disease are still lacking. The discovery of HCM-associated hub genes may help in diagnosis and offer a reliable tool for developing effective therapeutic strategies.MethodsWe examined HCM-based gene expression datasets (GSE36961) from the Gene Expression Omnibus (GEO) database for the identification of differentially expressed genes (DEGs), PPI network development, module screening, and shortlisting of hub genes via GEOR2, STRING, and Cytoscape. Moreover, we also used another HCM-based gene expression dataset (GSE32453) for the expression validation of hub genes. Following this, we constructed the lncRNA-cricRNA-miRNA-mRNA regulatory network after retrieving information from the miRTarBase, miRDB, and MiRcode databases. Finally, we used DAVID to perform functional and pathway analysis of the hub genes.ResultsFrom GSE36961, a total of the 262 most significant DEGs, including 162 down-regulated and 76 up-regulated, were identified between HCM patients and normal individuals. Among these DEGs, a total of 10 significantly down-regulated DEGs, including cluster of differentiation 14 (CD14), beta2 Integrin Gene (ITGB2), C1q subcomponent subunit B (C1QB), Cluster of Differentiation 163 (CD163), Hematopoietic Cell-Specific Lyn Substrate 1 (HCLS1), Arachidonate 5-Lipoxygenase Activating Protein (ALOX5AP), Pleckstrin (PLEK), Complement C1q C Chain (C1QC), Fc fragment Of IgE receptor Ig (FCER1G), and tyrosine kinase binding protein (TYROBP), were shortlisted as the hub genes. Pathway enrichment analysis showed that the identified hub genes were involved in the dysregulation of some diverse pathways in HCM patients. Such as, Pertussis, Complement and coagulation cascade, Legnionellosis, Asthma, Staphylococcus aureus infection, etc. Lastly, we also explored hub genes' regulatory 2 MicroRNAs (miRNAs, has-mir-7-5p and has-mir-27a-3p), one Long non-coding RNAs (lncRNA, OIP5-AS1-201), and one Circular RNA (cricRNA, CDR1as) via lncRNA-cricRNA-miRNA-mRNA regulatory network.ConclusionOur study revealed that ten hub genes (CD14, ITGB2, C1QB, CD163, HCLS1, ALOX5AP, PLEK, C1QC, FCER1G, and TYROBP) are involved in the development and progression of HCM. These genes can potentially be used as biomarkers and therapeutic targets for HCM patients.

Project description:A hypertrophic scar is the result of abnormal repair of the body after trauma. Histopathologically, it is mostly the result of the excessive proliferation of fibroblasts and the accumulation of extracellular matrix. Accumulating evidence has demonstrated that long non?coding RNAs (lncRNAs) have a critical role in the regulation of gene expression and in the pathogenesis of diseases. However, the roles of lncRNAs in hypertrophic scars have remained elusive. The present study investigated the profiles of differentially expressed lncRNAs between fibroblasts derived from a hypertrophic scar and normal skin, and explored the possible mechanisms underlying the development of hypertrophic scars. Microarray data indicated that 6,104 lncRNAs and 2,952 mRNAs were differentially expressed. A set of differentially expressed transcripts as confirmed by reverse transcription?quantitative polymerase chain reaction. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed to determine the principal functions of the significantly deregulated genes. Furthermore, associated expression networks, including subgroup analysis, competing endogenous RNAs (ceRNAs) and coding?noncoding co?expression networks were constructed using bioinformatics methods. The homology between differentially expressed lncRNAs and mRNAs was assessed and two exon lncRNA were selected to explore their regulatory mechanisms. The ceRNA network inferred that NR_125715 acted as a competing endogenous RNA, bound to microRNA (miR)?141?3p, miR?200a?3p and miR?29 to regulate the expression of the miRs' targets, including transforming growth factor ?2 (TGFB2). Similarly, NR_046402 acted as a competing endogenous RNA, which bound to miR?133a?3p.1 and miR?4469 to then regulate the expression of the miRs' targets, including DNA polymerase ?1, catalytic subunit (POLD1). In addition, co?expression analysis indicated that the expression of lncRNAs NR_125715 and NR_046402 was correlated with that of TGFB2 and POLD1 mRNA. The identification of these differentially expressed lncRNAs in the hypertrophic scar?derived fibroblasts in the present study, may provide novel insight into the functional interactions of lncRNA, miRNA and mRNA, and lead to novel theories for the pathogenesis and treatment of hypertrophic scars.

Dataset Information

Identification of circulating hub long noncoding RNAs associated with hypertrophic cardiomyopathy using weighted correlation network analysis.

Publications

Identification of circulating hub long noncoding RNAs associated with hypertrophic cardiomyopathy using weighted correlation network analysis.

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