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MiRNA-145 Regulates the Development of Congenital Heart Disease Through Targeting FXN
Lei Wang1, Danqiu Tian2, Jihua Hu2
1Department of Cardiology, Xi'an Children's Hospital, No. 69, Xiju RD, Lianhu District, Xi'an, 710003, Shaanxi, China. xawanglei@163.com.
Abstract:
Congenital heart disease (CHD) is the leading cause of death in infants in the world. The study of CHDs has come a long way since their classification and description. Although transcriptional programmes that are impaired in individuals with CHDs are being identified, the mechanisms of how these deficiencies translate to a structural defect are unknown. In this study, using high-throughput microarray analysis and molecular network analysis, FXN was identified to be the most differentially expressed key gene in CHD. By TargetScan analysis, we predicted FXN was the target gene of miRNA-145 and miRNA-182. Through real-time PCR analysis of clinical samples and experiments in cell lines, we confirmed that miRNA-145 but not miRNA-182 directly binds to the 3' UTR region of FXN and negatively regulates its expression. We further found that through targeting FXN, miRNA-145 regulates apoptosis and mitochondrial function. In general, our study confirmed the differentially expressed FXN regulates the development of CHD and the differential expression was under the control of miRNA-145. These results might provide new insight into the understanding of the CHD pathogenesis and may facilitate further therapeutic studies.
Insights
Congenital heart disease (CHD) involves altered FXN gene expression, regulated by miRNA-145. This finding offers new insights into CHD pathogenesis and potential therapeutic targets for infant heart defects.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Developmental Biology
Background:
- Congenital heart disease (CHD) is a leading cause of infant mortality worldwide.
- While impaired transcriptional programs in CHD are known, the mechanisms linking them to structural defects remain unclear.
- Understanding the molecular underpinnings of CHD is crucial for developing effective treatments.
Purpose of the Study:
- To identify key genes and regulatory mechanisms involved in congenital heart disease (CHD) pathogenesis.
- To investigate the role of FXN gene and its regulation by microRNAs in CHD.
- To explore the impact of miRNA-145/FXN interaction on cellular processes relevant to CHD.
Main Methods:
- High-throughput microarray and molecular network analysis to identify differentially expressed genes in CHD.
- Bioinformatic prediction (TargetScan) and experimental validation (real-time PCR) of microRNA-gene interactions.
- Cell line experiments to assess the functional impact of miRNA-145 on FXN expression, apoptosis, and mitochondrial function.
Main Results:
- FXN was identified as the most significantly differentially expressed gene in CHD.
- miRNA-145, but not miRNA-182, was confirmed to directly target and negatively regulate FXN expression.
- miRNA-145's regulation of FXN impacts apoptosis and mitochondrial function, key processes in CHD development.
Conclusions:
- FXN gene expression is differentially regulated in CHD, playing a role in its development.
- miRNA-145 is a key regulator of FXN expression in the context of CHD.
- These findings provide novel insights into CHD pathogenesis and suggest potential therapeutic avenues targeting the miRNA-145/FXN axis.
