Novel Genes Involved in Hypertrophic Cardiomyopathy: Data of Transcriptome and Methylome Profiling

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.

Genetic Mutations and Mitochondrial Redox Signaling as Modulating Factors in Hypertrophic Cardiomyopathy: A Scoping Review

“…Specifically, the DNA methylation in the promoter of the MYH7 gene is inversely correlated with beta-MyHC messenger RNA (mRNA) levels. This suggests that changes in methylation can alter the transcription of the mutated gene [ 26 ]. Moreover, the activation of chromatin-remodeling proteins, such as BRG1 and DPF3a, is associated with disease severity in patients with HCM [ 37 ].…”

“…In hearts affected by HCM, however, the increased energy demand during heart contraction can lead to metabolic disorders characterized by reduced ATP levels and increased intracellular ADP [ 26 , 54 ], with a preference for mitochondrial substrates over glucose [ 45 ]. This metabolic shift is also observed in patients with chronic myocardial infarction (CMI).…”

“…Metabolomic analyses have shown reduced cardiac bioenergetics and substrate utilization, indicating disturbances in energy metabolism that may contribute to the development of HCM-associated pathology [19]. In hearts affected by HCM, however, the increased energy demand during heart contraction can lead to metabolic disorders characterized by reduced ATP levels and increased intracellular ADP [26,54], with a preference for mitochondrial substrates over glucose [45]. This metabolic shift is also observed in patients with chronic myocardial infarction (CMI).…”

“…Mitochondrial dysfunction is associated with sarcomeric mutations that can significantly impact the tertiary structure and stability of proteins [ 23 , 26 ]. Inefficient sarcomere performance increases ATP demand, leading to energy depletion, chronic workload increases, and oxidative stress [ 27 ].…”

Clinical and genetic associations of asymmetric apical and septal left ventricular hypertrophy

“…Among loci shared between the septal and LVM GWASs, TTN is an established gene for familial DCM, GDF5 promotes cardiomyocyte survival, and loss of GDF5 is associated with LV dilation and contractile dysfunction 24 . Of the genes unique to septal mass, HIVEP3 is a transcription factor that is differentially methylated in HCM 26 , ESYT3 is part of a genetic module that is differentially expressed in arrhythmogenic cardiomyopathy 27 , and HMGA1 regulates cardiomyocyte growth with roles in concentric cardiac hypertrophy, myocardial infarction, and inflammation [28][29][30] .…”