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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Systematic identification and analysis of dysregulated miRNA and transcription factor feed-forward loops in
Hongbo Shi1, Jiayao Li1, Qiong Song1
1College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China.
Insights
Researchers identified 316 dysregulated microRNA-transcription factor feed-forward loops (FFLs) in hypertrophic cardiomyopathy (HCM). This study also revealed potential biomarkers for diagnosing and treating this common genetic cardiovascular disease.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Medicine
Background:
- Hypertrophic cardiomyopathy (HCM) is the most prevalent genetic cardiovascular disorder.
- Existing research on HCM has identified some related genes and microRNAs (miRNAs), but the intricate regulatory mechanisms involving miRNAs and transcription factors (TFs) remain incompletely understood.
Purpose of the Study:
- To systematically investigate the molecular regulatory mechanisms between miRNAs and TFs in HCM.
- To develop and validate a novel method for identifying dysregulated miRNA-TF feed-forward loops (FFLs) in HCM.
- To identify potential biomarkers for HCM diagnosis and treatment.
Main Methods:
- Developed a novel computational method integrating sample-matched miRNA and gene expression profiles with experimentally verified TF-target gene and miRNA-target gene interactions.
- Identified and analyzed dysregulated miRNA-TF FFLs in HCM.
- Performed subpathway enrichment analysis to compare the novel method with existing approaches.
- Systematically analyzed the global architecture and features of gene regulation by miRNAs and TFs in HCM.
- Identified candidate biomarkers using a discovery cohort of 126 samples.
Main Results:
- Identified 316 dysregulated miRNA-TF FFLs significantly associated with HCM.
- The novel method demonstrated superior performance compared to existing methods in subpathway enrichment analysis.
- The FFL comprising hsa-miR-17-5p, FASN, and STAT3 was inferred to play a crucial role in HCM.
- Identified two panels of biomarkers: three TFs (CEBPB, HIF1A, STAT3) and four miRNAs (hsa-miR-155-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-181a-5p).
- These biomarker panels effectively differentiated HCM patients from healthy controls.
Conclusions:
- The study provides a comprehensive analysis of dysregulated miRNA-TF FFLs in HCM, offering valuable targets for further experimental investigation.
- The identified FFLs and candidate biomarkers contribute to a deeper understanding of HCM pathogenesis.
- The proposed biomarkers show promise for improving the diagnosis and treatment strategies for HCM.
Abstract:
Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease. Although some genes and miRNAs related with HCM have been studied, the molecular regulatory mechanisms between miRNAs and transcription factors (TFs) in HCM have not been systematically elucidated. In this study, we proposed a novel method for identifying dysregulated miRNA-TF feed-forward loops (FFLs) by integrating sample matched miRNA and gene expression profiles and experimentally verified interactions of TF-target gene and miRNA-target gene. We identified 316 dysregulated miRNA-TF FFLs in HCM, which were confirmed to be closely related with HCM from various perspectives. Subpathway enrichment analysis demonstrated that the method was outperformed by the existing method. Furthermore, we systematically analysed the global architecture and feature of gene regulation by miRNAs and TFs in HCM, and the FFL composed of hsa-miR-17-5p, FASN and STAT3 was inferred to play critical roles in HCM. Additionally, we identified two panels of biomarkers defined by three TFs (CEBPB, HIF1A, and STAT3) and four miRNAs (hsa-miR-155-5p, hsa-miR-17-5p, hsa-miR-20a-5p, and hsa-miR-181a-5p) in a discovery cohort of 126 samples, which could differentiate HCM patients from healthy controls with better performance. Our work provides HCM-related dysregulated miRNA-TF FFLs for further experimental study, and provides candidate biomarkers for HCM diagnosis and treatment.
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