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Published on: September 15, 2018
Integrated Multi-omics Analysis of Hub Genes and miRNA Interactions in Hypertrophic Cardiomyopathy
Huanhuan Hu1,2, Ziheng Yu1,2, Kongjie Lu1,2
1Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, 313000, China.
Insights
This study identifies six key genes (IREB2, PTPN11, IQGAP1, PGM2, DIS3, GFPT1) downregulated in hypertrophic cardiomyopathy (HCM). These genes, regulated by miRNAs, show potential as diagnostic biomarkers and therapeutic targets for HCM.
Area of Science:
- Cardiovascular Research
- Genomics
- Molecular Biology
Background:
- Hypertrophic Cardiomyopathy (HCM) is a cardiac disorder characterized by heart muscle thickening.
- Identifying molecular mechanisms underlying HCM is crucial for developing effective treatments.
Purpose of the Study:
- To identify differentially expressed genes (DEGs) and key hub genes in Hypertrophic Cardiomyopathy (HCM).
- To explore the potential of these genes as diagnostic biomarkers and therapeutic targets for HCM.
Main Methods:
- Analysis of three Gene Expression Omnibus (GEO) datasets to identify DEGs in HCM.
- Protein-protein interaction (PPI) network analysis using Cytoscape to identify hub genes.
- Validation of hub gene expression using RT-qPCR and Western blot.
- Bioinformatic analyses including gene enrichment, miRNA prediction, and molecular docking.
Main Results:
- Identified 21 common downregulated genes, with six key hub genes: IREB2, PTPN11, IQGAP1, PGM2, DIS3, and GFPT1.
- Hub genes are involved in energy metabolism and growth factor signaling pathways.
- Validation confirmed significant downregulation of hub genes in HCM, with high diagnostic potential shown by ROC curve analysis.
- Six miRNAs were found to be upregulated and potentially regulate the identified hub genes.
Conclusions:
- Downregulation of specific hub genes and miRNA-mediated pathway dysregulation are implicated in HCM progression.
- The identified hub genes (IREB2, PTPN11, IQGAP1, PGM2, DIS3, GFPT1) show promise as biomarkers for HCM diagnosis.
- These genes and their regulatory pathways represent potential targets for novel therapeutic strategies in HCM treatment.
Background:
Hypertrophic Cardiomyopathy (HCM) is a complex cardiac disorder marked by the thickening of the heart muscle.
Methods:
HCM and normal control cell lines were cultured in DMEM with 12.5% FBS and 1% penicillin-streptomycin at 37°C and 5% CO2. Differentially expressed genes (DEGs) were identified from GSE32453, GSE53408, and GSE113439 datasets using the limma package in R. Hub genes were determined through protein-protein interaction (PPI) network and Cytoscape analysis and validated via Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) and Western blot analysis. Gene enrichment, miRNA predictions, drug prediction, and molecular docking analyses were conducted for functional enrichment and to explore hub gene-associated drugs.
Results:
To identify DEGs and hub genes implicated in HCM, we analyzed three Gene Expression Omnibus (GEO) datasets (GSE32453, GSE53404, and GSE1134439), extracting the top 1000 DEGs. Venn analysis revealed 21 common down-regulated genes. PPI analysis identified these six as key hub genes, including Iron Response Element Binding Protein 2 (IREB2), Protein Tyrosine Phosphatase, Non-Receptor Type 11 (PTPN11), IQ Motif Containing GTPase Activating Protein 1 (IQGAP1), Phosphoglucomutase 2 (PGM2), DIS3 RNA Exonuclease 3' to 5' (DIS3), Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1) in HCM patients. Gene enrichment analysis highlighted the involvement of these genes in cellular functions such as energy metabolism and growth factor signaling, suggesting their role in the disease's progression. Validation using an additional dataset (GSE36961) confirmed significant down-regulation of all hub genes in HCM samples, supported by Receiver Operating Characteristic (ROC) curve analysis that demonstrated their diagnostic potential. Furthermore, miRNA analysis identified six up-regulated miRNAs (miR-124, miR-29b, miR-330, miR-34a, miR-375, and miR-451) that likely contribute to the dysregulation of these hub genes. Drug prediction analysis identified various potential therapeutic compounds targeting these hub genes. Molecular docking revealed favorable binding affinities, supporting the therapeutic potential of these drugs in modulating hub gene activity.
Discussion:
These findings demonstrate that HCM progression involves coordinated downregulation of hub genes and miRNA-mediated dysregulation of metabolic and signaling pathways. The integration of bioinformatics, validation assays, and drug docking suggests a strong translational potential for biomarker discovery and targeted therapy.
Conclusion:
Our findings suggest that IREB2, PTPN11, IQGAP1, PGM2, DIS3, and GFPT1 hub genes and their associated regulatory pathways may serve as biomarkers and therapeutic targets for HCM, potentially improving diagnosis and treatment strategies.
