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. 2024 Jan 23;19(1):20230880.
doi: 10.1515/med-2023-0880. eCollection 2024.

Transcriptome analysis of effects of Tecrl deficiency on cardiometabolic and calcium regulation in cardiac tissue

Shujia Lin  1 , Shun Chen  1 , Qiuping Lin  1 , Tingting Xiao  1   2 , Cuilan Hou  1   2 , Lijian Xie  1   3
Affiliations

Transcriptome analysis of effects of Tecrl deficiency on cardiometabolic and calcium regulation in cardiac tissue

Shujia Lin et al. Open Med (Wars). .

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a hereditary heart disease characterized by bidirectional or polymorphic ventricular tachycardia and an increased risk of sudden cardiac death. Although trans-2,3-enoyl-CoA reductase like (TECRL) is a newly reported pathogenic gene leading to CPVT that can influence intracellular calcium regulation, the unidentified mechanism underlying the pathogenesis of TECRL deficiency-mediated CPVT remains mainly elusive. In the present study, Tecrl knockout (KO) mice were established and the differentially expressed genes (DEGs) were investigated by RNA-sequencing from the heart tissues. In addition, 857 DEGs were identified in Tecrl KO mice. Subsequently, a weighted gene co-expression network analysis was conducted to discern the pivotal pathways implicated in the Tecrl-mediated regulatory network. Moreover, pathway mapping analyses demonstrated that essential metabolism-related pathways were significantly enriched, notably the fatty acid metabolic process and calcium regulation. Collectively, the data suggested a synergistic relationship between Tecrl deficiency and cardiometabolic and calcium regulation during the development of CPVT. Therefore, further studies on the potential function of TECRL in cardiac tissues would be beneficial to elucidate the pathogenesis of CPVT.

Keywords: RNA-seq; Tecrl; WGCNA; catecholaminergic polymorphic ventricular tachycardia.

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Conflict of interest statement

Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
TECRL protein identification and functional enrichment analysis of DEGs. (a) Representative western blots of TECRL in different tissues of WT mice. (b) PCA plot of male and female mice samples. There were four groups, three mice in each group. An average of 5.28 ±  1.37 million raw reads per sample were obtained and PCA shows distinct patterns among groups. (c) Volcano plot of DEGs of male Tecrl −/− mice. Each point represents a single gene. Grey points represent the genes that have no significant changes, while the orange dots indicate the genes that are upregulated and green dots indicate the genes that are downregulated. (|log2(FoldChange)| ≥0.58, P value <0.05). (d) GO enriched terms associated with DEGs in male Tecrl −/− mice. (e) KEGG enriched pathways related to DEGs in male Tecrl −/− mice. BP, biological process; CC, cellular component; MF, molecular function.
Figure 2
Figure 2
Hub gene selection and enrichment analysis: (a) GESA analysis of fatty acid beta-oxidation pathway, (b) GESA analysis of calcium regulation of cardiac cells pathway, (c) heatmap of fatty acid metabolism related genes in Tecrl −/− samples, and (d) heatmap of calcium handling related genes in Tecrl −/− samples.
Figure 3
Figure 3
WGCNA revealing gene co-expression networks. (a) Utilizing WGCNA analysis, the dendrogram depicted the clusters of genes that were differentially expressed, based on various metrics. Each branch of the dendrogram represented an individual gene, while the colors beneath the branches represented a co-expression module. (b) The heatmap illustrated the correlation between gene modules and group phenotypes. The correlation coefficient within each cube indicated the degree of correlation between gene modules and traits, with a decreasing gradient from red to blue. (c) The functional enrichment analysis was conducted on Tecrl KO-related hub genes from the midnight blue and royal blue modules. (d) The DisGeNET terms of hub genes were enriched. (e) The hub genes underwent GO enrichment. The horizontal axis depicts the P-value of GO terms on Metascape using default parameters. (f) The top Molecular Complex Detection algorithm (MCODE) terms of hub genes related to Tecrl KO were identified. A network was formed by the protein–protein interactions (PPI) among Tecrl KO-related hub genes from the red module. The MCODE was utilized to detect the connected network components.
Figure 4
Figure 4
Tecrl deletion leads to significant representative changes. (a) TECRL expression in healthy and BrS patients. (b–e) The graphs of healthy group and Brs group showing a positive correlation of TECRL expression and (b) UCP3, (c) UCP2, (d) CPT2, and (e) APOA1. (f) The heatmap of 48 fatty acid metabolism related genes in BrS. (g) Changes in the mRNA level of Apoa1, Fabp5, and Camk2b.
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