Identification of circRNA–miRNA–mRNA Regulatory Network and Crucial Signaling Pathway Axis Involved in Tetralogy of Fallot

Abstract

Tetralogy of Fallot (TOF) is one of the most common cyanotic congenital heart diseases (CHD) worldwide; however, its pathogenesis remains unclear. Recent studies have shown that circular RNAs (circRNAs) act as “sponges” for microRNAs (miRNAs) to compete for endogenous RNA (ceRNA) and play important roles in regulating gene transcription and biological processes. However, the mechanism of ceRNA in TOF remains unclear. To explore the crucial regulatory connections and pathways of TOF, we obtained the human TOF gene, miRNA, and circRNA expression profiling datasets from the Gene Expression Omnibus (GEO) database. After data pretreatment, differentially expressed mRNAs (DEmRNAs), microRNAs (DEmiRNAs), and circRNAs (DEcircRNAs) were identified between the TOF and healthy groups, and a global triple ceRNA regulatory network, including circRNAs, miRNAs, and mRNAs based on the integrated data, was constructed. A functional enrichment analysis was performed on the Metascape website to explore the biological functions of the selected genes. Then, we constructed a protein-protein interaction (PPI) network and identified seven hub genes using the cytoHubba and MCODE plug-ins in the Cytoscape software, including BCL2L11, PIK3R1, SOCS3, OSMR, STAT3, RUNX3, and IL6R. Additionally, a circRNA–miRNA–hub gene subnetwork was established, and its enrichment analysis results indicated that the extrinsic apoptotic signaling pathway, JAK-STAT signaling pathway and PI3K-Akt signaling pathway may be involved in the pathogenesis of TOF. We further identified the hsa_circ_000601/hsa-miR-148a/BCL2L11 axis as a crucial signaling pathway axis from the subnetwork. This study provides a novel regulatory network for the pathogenesis of TOF, revealing the possible molecular mechanisms and crucial regulatory pathways that may provide new strategies for candidate diagnostic biomarkers or potential therapeutic targets for TOF.

Epigenetic Modification Factors and microRNAs Network Associated with Differentiation of Embryonic Stem Cells and Induced Pluripotent Stem Cells toward Cardiomyocytes: A Review

“…The data support the idea that the CHD patients’ illness state is caused by a changed miRNA expression. In another study, it was revealed that hsa-miR-148a and BCL2L11 are linked to cardiomyocyte apoptosis and Hsa-miR-148a might affect BCL2L11 [ 240 ]. Recent findings have shown that miR-153-3p targets βII spectrin, which has a negative effect on myocardial development [ 241 ].…”

The right ventricle in tetralogy of Fallot: adaptation to sequential loading

“…A recent study aimed to generate a circRNA-miRNA-mRNA network in TOF. They analyzed three datasets available in GEO databases comparing profiles and identified 29 miRNA, 13 circRNAs and 88 mRNAs ( 138 ). Interestingly, a comparison between overlapping miRNA profiles in four other studies yielded two miRNAs that were identified in all 4 studies and 5 miRNAs that were identified in at least 3 of the 4 studies ( Table 1 ) ( 139 – 142 ).…”

“…Interestingly, a comparison between overlapping miRNA profiles in four other studies yielded two miRNAs that were identified in all 4 studies and 5 miRNAs that were identified in at least 3 of the 4 studies (Table 1) (139-142). MiR-222, also identified in the network by Kan et al has been associated with exercise-induced myocardial adaptation, atrial fibrillation, is involved in function of L-type calcium channels and is a target of angiogenesis and proliferation via ERBB4 and HIF1α (138,(143)(144)(145)(146). MiR-194 has been linked to the p53 pathway and may be involved in pulmonary angiogenesis (147).…”

Identification and analysis of inflammation-related biomarkers in tetralogy of Fallot

“…), and epigenetic modi cations based on gene methylation (e.g., methylation of LINE1, NKX2-5, ZFPM2, etc.) [5][6][7][8][9]. The environmental factors include physical factors (such as ionizing radiation and noise pollution), chemical factors (such as long-term exposure to organic solvents, cocaine, etc.…”