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The Integrative Regulatory Network of circRNA, microRNA, and mRNA in Atrial Fibrillation.

ABSTRACT: Atrial fibrillation (AF) is the most common irregular heart rhythm which influence approximately 1-2% of the general population. As a potential factor for ischemic stroke, AF could also cause heart failure. The mechanisms behind AF pathogenesis is complex and remains elusive. As a new category of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been known as the key of developmental processes, regulation of cell function, pathogenesis of heart diseases and pathological responses which could provide novel sight into the pathogenesis of AF. circRNAs function as modulators of microRNAs in cardiac disease. To investigate the regulatory mechanism of circRNA in AF, especially the complex interactions among circRNA, microRNA and mRNA, we collected the heart tissues from three AF patients and three healthy controls and profiled their circRNA expressions with circRNA Microarray. The differentially expressed circRNAs were identified and the biological functions of their interaction microRNAs and mRNAs were analyzed. Our results provided novel insights of the circRNA roles in AF and proposed highly possible interaction mechanisms among circRNAs, microRNAs, and mRNAs.

SUBMITTER: Jiang S

PROVIDER: S-EPMC6584754 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The Integrative Regulatory Network of circRNA, microRNA, and mRNA in Atrial Fibrillation.

Jiang Shengyang S Guo Changfa C Zhang Wei W Che Wenliang W Zhang Jie J Zhuang Shaowei S Wang Yiting Y Zhang Yangyang Y Liu Ban B

Frontiers in genetics 20190613

Atrial fibrillation (AF) is the most common irregular heart rhythm which influence approximately 1-2% of the general population. As a potential factor for ischemic stroke, AF could also cause heart failure. The mechanisms behind AF pathogenesis is complex and remains elusive. As a new category of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) have been known as the key of developmental processes, regulation of cell function, pathogenesis of heart diseases and pathological responses which cou ...[more]

PMID: 31249590

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Project description:Atrial fibrillation (AF) is a chronic and progressive disease, with advancing age, the morbidity of which will increase exponentially. Circular ribonucleic acids (RNAs; circRNAs) have gained a growing attention in the development of AF in recent years. The purpose of this study is to explore the mechanism of circRNA regulation in AF, in particular, the intricate interactions among circRNA, microRNA (miRNA), and messenger RNA (mRNA). Three datasets (GSE129409, GSE68475, and GSE79768) were obtained from the Gene Expression Omnibus database to screen differentially expressed (DE) circRNAs, DE miRNAs, and DE mRNAs in AF, respectively. Based on circRNA-miRNA pairs and miRNA-mRNA pairs, a competing endogenous RNAs (ceRNAs) network was built. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis of DE mRNAs in the network were performed and protein-protein interaction (PPI) networks were established to identify hub genes. Finally, a circRNA-miRNA-hub gene subnetwork was constructed. A total of 103 DE circRNAs, 16 DE miRNAs, and 110 DE mRNAs were screened in AF. Next, ceRNAs network in AF was constructed with 3 upregulated circRNAs, 2 downregulated circRNAs, 2 upregulated miRNAs, 2 downregulated miRNAs, 17 upregulated mRNAs, and 24 downregulated mRNAs. Thirty GO terms and 6 KEGG pathways were obtained. Besides, 6 hub genes (C-X-C chemokine receptor type 4 [CXCR4], C-X-C chemokine receptor type 2 [CXCR2], C-X-C motif chemokine 11 [CXCL11], neuromedin-U, B1 bradykinin receptor, and complement C3) were screened from constructing a PPI network. Finally, a circRNA-miRNA-hub gene subnetwork with 10 regulatory axes was constructed to describe the interactions among the differential circRNAs, miRNA, and hub genes. We speculated that hsa_circRNA_0056281/hsa_circRNA_0006665 -hsa-miR-613-CXCR4/CXCR2/CXCL11 regulatory axes and hsa_circRNA_0003638-hsa-miR-1207-3p-CXCR4 regulatory axis may be associated with the pathogenesis of AF.

Project description:BackgroundAtrial fibrillation (AF) is one of the most prevalent arrhythmias, characterized by a high risk of heart failure and embolic stroke. Competing endogenous RNA network has been reported to play an important role in cardiovascular diseases. The main objective of the present study was to construct a circRNA-miRNA-mRNA-mediated network and explore the potential function in AF.MethodsThe microarray data of circRNA, miRNA, and mRNA in AF were downloaded from the Gene Expression Omnibus database. The RobustRankAggreg method was used to screen the different expression circRNAs(DECs). Then the circRNA-miRNA-mRNA-mediated network was constructed by using the CircInteractome database and the miRWalk online tool. A quantitative real-time polymerase chain reaction was used to detect the circRNA expression level in plasma. The left atrial fibrosis was evaluated with the left atrial low voltage area (LVA) by using left atrial voltage matrix mapping.ResultsThree DECs (hsa_circRNA_102461, hsa_circRNA_103693, and hsa_circRNA_059880) and 4 miRNAs were screened. Then a circRNA-miRNA-mRNA-mediated network was constructed, which included 2 circRNAs, 4 miRNAs, and 83 genes. Furthermore, the plasma's hsa_circ_0070391 expression level was confirmed to be upregulated and positively correlated with left atrial fibrosis in AF (r = 0.88, P < 0.001), whereas hsa_circ_0003935 was downregulated. Moreover, the ROC curve analysis revealed hsa_circ_0070391 and hsa_circ_0003935 could differentiate AF from the healthy controls with an AUC of 0.95 (95% sensitivity and 90% specificity) and 0.86 (70% sensitivity and 75% specificity), respectively. Finally, the free of atrial tachyarrhythmia rate was dramatically lower in the hsa_circ_0070391 high expression group than in the low expression group post catheter ablation (70.0 vs. 90.0%, p = 0.04).ConclusionThis study provides a novel insight to further understand the AF pathogenesis from the perspective of the circRNA-miRNA-mRNA network, suggesting that plasma circRNAs could serve as a novel atrial fibrosis and prognosis biomarker for AF.

Project description:Viral noncoding RNAs have acquired increasing prominence as important regulators of infection and mediators of pathogenesis. Circular RNAs (circRNAs) generated by backsplicing events have been identified in several oncogenic human DNA viruses. Here, we show that Merkel cell polyomavirus (MCV), the etiologic cause of ?80% of Merkel cell carcinomas (MCCs), also expresses circular RNAs. By RNase R-resistant RNA sequencing, four putative circRNA backsplice junctions (BSJs) were identified from the MCV early region (ER). The most abundantly expressed MCV circRNA, designated circMCV-T, is generated through backsplicing of all of ER exon II to form a 762-nucleotide (nt) circular RNA molecule. Curiously, circMCV-T, as well as two other less abundantly expressed putative MCV circRNAs, overlaps in a complementary fashion with the MCV microRNA (miRNA) locus that encodes MCV-miR-M1. circMCV-T is consistently detected in concert with linear T antigen transcripts throughout infection, suggesting a crucial role for this RNA molecule in the regulatory functions of the early region, known to be vital for viral replication. Knocking out the hairpin structure of MCV-miR-M1 in genomic early region expression constructs and using a new high-efficiency, recombinase-mediated, recircularized MCV molecular clone demonstrates that circMCV-T levels decrease in the presence of MCV-miR-M1, underscoring the interplay between MCV circRNA and miRNA. Furthermore, circMCV-T partially reverses the known inhibitory effect of MCV-miR-M1 on early gene expression. RNase R-resistant RNA sequencing of lytic rat polyomavirus 2 (RatPyV2) identified an analogously located circRNA, stipulating a crucial, conserved regulatory function of this class of RNA molecules in the family of polyomaviruses.IMPORTANCE Covalently closed circular RNAs were recently described in the human DNA tumor viruses Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV). Here, we show that MCV, another DNA tumor virus, generates circRNAs from its early regulatory region in concert with T antigen linear transcripts. MCV circMCV-T interacts with another MCV noncoding RNA, miR-M1, to functionally modulate early region transcript expression important for viral replication and long-term episomal persistence. This work describes a dynamic regulatory network integrating circRNA/miRNA/mRNA biomolecules and underscores the intricate functional modulation between several classes of polyomavirus-encoded RNAs in the control of viral replication.

Dataset Information

The Integrative Regulatory Network of circRNA, microRNA, and mRNA in Atrial Fibrillation.

Publications

The Integrative Regulatory Network of circRNA, microRNA, and mRNA in Atrial Fibrillation.

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