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DNA methylome and transcriptome profiling reveal key electrophysiology and immune dysregulation in hypertrophic
Xiaoyan Li1, Hailang Fan2, Xiantao Song3,4
1Beijing Anzhen Hospital, Beijing Institute of Heart, Lung and Blood Vessel Diseases, Capital Medical University, Beijing, China.
Insights
Hypertrophic cardiomyopathy (HCM) shows altered DNA methylation (DNAme) despite normal gene transcription. This epigenetic dysregulation impacts immune and muscle functions, offering potential therapeutic targets for this inherited heart disease.
Area of Science:
- Cardiovascular Genetics
- Epigenetics
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac condition.
- A comprehensive understanding of the DNA methylation (DNAme) landscape in HCM myocardium is lacking.
- DNAme plays a crucial role in regulating gene expression and cellular function.
Purpose of the Study:
- To investigate the DNA methylation profile of HCM myocardium.
- To identify aberrant DNAme patterns associated with altered myocardial function in HCM.
- To explore the relationship between DNAme alterations, gene expression, and functional pathways in HCM.
Main Methods:
- Integrated analysis of DNA methylation and transcriptome profiles from HCM and normal myocardium.
- Chromosomal distribution analysis of hypermethylated and hypomethylated sites.
- Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.
- Protein-protein interaction (PPI) network analysis.
- Estimation of immune cell infiltration.
Main Results:
- HCM myocardium exhibits distinct DNA methylation profiles compared to normal myocardium, despite similar transcription levels of methylation-related genes.
- Differentially methylated sites in HCM show unique chromosomal distributions and functional enrichment of correlated genes, particularly in immune cell and muscle system processes.
- The calcium signaling pathway was significantly enriched in both DNAme-altered and differentially expressed genes.
- PPI analysis revealed immune response (involving ESR1) and cardiac electrophysiology as key functional clusters.
- Intelliectin-1 (ITLN1) was downregulated and hypermethylated in HCM, with reduced immune cell diversity observed.
Conclusions:
- Aberrant DNA methylation is a key feature of hypertrophic cardiomyopathy, impacting crucial cellular functions.
- The identified DNAme alterations and associated pathways, including immune response and calcium signaling, represent potential therapeutic targets for HCM.
- Combined DNAme and transcriptome profiling offers a promising approach for understanding HCM pathogenesis and developing novel treatments.
Abstract:
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease. However, a detailed DNA methylation (DNAme) landscape has not yet been elucidated. Our study combined DNAme and transcriptome profiles for HCM myocardium and identify aberrant DNAme associated with altered myocardial function in HCM. The transcription of methylation-related genes did not significantly differ between HCM and normal myocardium. Nevertheless, the former had an altered DNAme profile compared with the latter. The hypermethylated and hypomethylated sites in HCM tissues had chromosomal distributions and functional enrichment of correlated genes differing from those of their normal tissue counterparts. The GO analysis of network underlying the genes correlated with DNAme alteration and differentially expressed genes (DEGs) shows functional clusters centred on immune cell function and muscle system processes. In KEGG analysis, only the calcium signalling pathway was enriched either by the genes correlated with changes in DNAme or DEGs. The protein-protein interactions (PPI) underlying the genes altered at both the DNAme and transcriptional highlighted two important functional clusters. One of these was related to the immune response and had the estrogen receptor-encoding ESR1 gene as its node. The other cluster comprised cardiac electrophysiology-related genes. Intelliectin-1 (ITLN1), a component of the innate immune system, was transcriptionally downregulated in HCM and had a hypermethylated site within 1500 bp upstream of the ITLN1 transcription start site. Estimates of immune infiltration demonstrated a relative decline in immune cell population diversity in HCM. A combination of DNAme and transcriptome profiles may help identify and develop new therapeutic targets for HCM.
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