期刊
CLINICAL EPIGENETICS
卷 13, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13148-021-01043-3
关键词
HCM; MYBPC3; Histone acetylome; Transcriptome; Proteome; Transcription factors
资金
- Netherlands Foundation for Cardiovascular Excellence
- NWO VENI Grant [016.176.136]
- NWO VIDI Grants [91714302, 016096359, 91715303]
- ZonMW-NWO VICI Grant [91818902]
- Erasmus MC fellowship grant
- RM fellowship grant of the UMC Utrecht
- Wilhelmina Children's Hospital [OZF/14]
- Netherlands Cardiovascular Research Initiative: An initiative
- UCL Hospitals NIHR Biomedical Research Centre
- Starting Grant (STEMCARDIORISK) from European Research Council under the European Union's Horizon 2020 Research and Innovation Program (H2020 European Research Council) [638030]
- Dutch Heart Foundation [CVON2014-40 DOSIS, CVON2014-11 RECONNECT, Dekker 2015T041]
- European Research Council (ERC) [638030] Funding Source: European Research Council (ERC)
Through integrating histone acetylome, transcriptome, and proteome profiles, we identified major effector genes and protein networks driving 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.
Background Hypertrophic 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. Results Using 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. Conclusions By 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.
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