Abstract
BackgroundHypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. However, little is known about the upstream pathways and key regulators causing the disease. Therefore, we employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts.ResultsUsing H3K27ac ChIP-seq and RNA-seq we obtained 9310 differentially acetylated regions and 2033 differentially expressed genes, respectively, between 13 HCM and 10 control hearts. We obtained 441 differentially expressed proteins between 11 HCM and 8 control hearts using proteomics. By integrating multi-omics datasets, we identified a set of DNA regions and genes that differentiate HCM from control hearts and 53 protein-coding genes as the major contributors. This comprehensive analysis consistently points toward altered extracellular matrix formation, muscle contraction, and metabolism. Therefore, we studied enriched transcription factor (TF) binding motifs and identified 9 motif-encoded TFs, including KLF15, ETV4, AR, CLOCK, ETS2, GATA5, MEIS1, RXRA, and ZFX. Selected candidates were examined in stem cell-derived cardiomyocytes with and without mutated MYBPC3. Furthermore, we observed an abundance of acetylation signals and transcripts derived from cardiomyocytes compared to non-myocyte populations.ConclusionsBy integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks that drive the pathological changes in HCM with mutated MYBPC3. Our work identifies 38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 TFs as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets.
Highlights
Hypertrophic cardiomyopathy (HCM), characterized by thickening of the myocardium that is not explained by abnormal loading conditions, is the most common inherited cardiac disease [1]
38 highly affected protein-coding genes as potential plasma HCM biomarkers and 9 transcription factor (TF) as potential upstream regulators of these pathomechanisms that may serve as possible therapeutic targets
We identified 4,226 regions presented higher acetylation levels and 5,084 regions presented lower acetylation levels in HCM versus control hearts (Padj < 0.05, Fig. 1b, (See figure on page.) Fig. 1 Pairwise analyses using DESeq2 and integrative analyses using unsupervised two-way orthogonal partial least squares (O2PLS) in all samples. a An overview of the study design. b Upper plot: MA plot showing the hyper- and hypoacetylation regions in HCM samples compared to controls using DESeq2; bottom plot: principal component analysis (PCA) plot showing the separation between HCM and control samples based on the top differentially acetylated regions using DESeq2
Summary
Hypertrophic cardiomyopathy (HCM), characterized by thickening of the myocardium that is not explained by abnormal loading conditions, is the most common inherited cardiac disease [1]. More than 1,500 associated mutations, primarily in genes encoding parts of the sarcomere, such as MYBPC3, MYH7, and TNNT2, have been identified. HCM is a heterogeneous disease as the onset, the disease phenotype, and the severity of the clinical presentations differ greatly among mutation carriers [3]. Different mutated genes exhibit distinct biological impact on cellular contractility, energy metabolism, and sarcomeric protein expression in HCM hearts [4]. Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the cardiac muscle, frequently caused by mutations in MYBPC3. We employed a multi-omics approach to study the pathomechanisms underlying HCM comparing patient hearts harboring MYBPC3 mutations to control hearts
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