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Published on: August 8, 2022
Novel Genes Involved in Hypertrophic Cardiomyopathy: Data of Transcriptome and Methylome Profiling
Ivan Kiselev1,2, Maxim Kozin1,2, Natalia Baulina1,2
1E.I. Chazov National Medical Research Center for Cardiology, Moscow 121552, Russia.
Insights
New research reveals novel genes linked to hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. DNA methylation and gene expression changes in HCM hearts suggest a role for neurogenesis and synapse-functioning genes in disease development.
Area of Science:
- Cardiovascular Genetics
- Epigenetics
- Molecular Biology
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary inherited cardiac condition.
- Significant genetic and phenotypic variability complicates HCM understanding.
- The precise mechanisms driving HCM pathogenesis remain under investigation.
Purpose of the Study:
- To identify novel genes implicated in HCM development.
- To investigate the interplay between gene expression and DNA methylation in HCM.
- To explore the functional roles of identified genes in cardiac hypertrophy.
Main Methods:
- Analysis of gene expression profiles (transcriptome) in hypertrophied HCM patient myocardia.
- Analysis of DNA methylation profiles (methylome) in the same patient samples.
- Integration of transcriptomic and methylomic data using gene ontology enrichment and intersection analysis.
Main Results:
- Transcriptome analysis revealed 193 differentially expressed genes (DEGs), predominantly underexpressed in HCM.
- Methylome analysis identified 1755 differentially methylated positions (DMPs), mostly hypomethylated.
- Eight common genes showed expression correlated with neighboring DMP methylation; four (AUTS2, BRSK2, PRRT1, SLC17A7) were underexpressed and linked to neurogenesis/synapse function.
Conclusions:
- The study implicates novel genes, particularly those involved in neurogenesis and synapse function, in HCM pathogenesis.
- Aberrant DNA methylation may regulate the expression of these innervation-associated genes in HCM.
- Findings offer new insights into HCM heterogeneity and suggest potential avenues for future research.
Abstract:
Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease; its pathogenesis is still being intensively studied to explain the reasons for the significant genetic and phenotypic heterogeneity of the disease. To search for new genes involved in HCM development, we analyzed gene expression profiles coupled with DNA methylation profiles in the hypertrophied myocardia of HCM patients. The transcriptome analysis identified significant differences in the levels of 193 genes, most of which were underexpressed in HCM. The methylome analysis revealed 1755 nominally significant differentially methylated positions (DMPs), mostly hypomethylated in HCM. Based on gene ontology enrichment analysis, the majority of biological processes, overrepresented by both differentially expressed genes (DEGs) and DMP-containing genes, are involved in the regulation of locomotion and muscle structure development. The intersection of 193 DEGs and 978 DMP-containing genes pinpointed eight common genes, the expressions of which correlated with the methylation levels of the neighboring DMPs. Half of these genes (AUTS2, BRSK2, PRRT1, and SLC17A7), regulated by the mechanism of DNA methylation, were underexpressed in HCM and were involved in neurogenesis and synapse functioning. Our data, suggesting the involvement of innervation-associated genes in HCM, provide additional insights into disease pathogenesis and expand the field of further research.
