Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression
Background Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease where the most frequently associated mutations occur in the myosin‐binding protein C (MYBPC3) sarcomere‐associated gene. HCM is also a common veterinary clinical problem in certain cat breeds such as Maine Coons and Rag...
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Wiley
2025-01-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.035780 |
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| author | Samia A. Ali Gayani Perera Jason Laird Rebecca Batorsky Martin S. Maron Victor N. Rivas Joshua A. Stern Samantha Harris Michael T. Chin |
| author_facet | Samia A. Ali Gayani Perera Jason Laird Rebecca Batorsky Martin S. Maron Victor N. Rivas Joshua A. Stern Samantha Harris Michael T. Chin |
| author_sort | Samia A. Ali |
| collection | DOAJ |
| description | Background Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease where the most frequently associated mutations occur in the myosin‐binding protein C (MYBPC3) sarcomere‐associated gene. HCM is also a common veterinary clinical problem in certain cat breeds such as Maine Coons and Ragdolls, also most associated with mutations in MYBPC3. Mouse models of HCM in which Mybpc3 mutations are introduced recapitulate some, but not all, features of human HCM. Methods and Results To elucidate the common and distinctive pathological pathways across species and foster a greater understanding of the concordance of mouse HCM models to clinical mybpc3‐associated HCM, we generated single nuclei RNA‐sequencing data sets from feline, human, and murine heart tissue carrying MYBPC3 variants. Numerous genes were differentially expressed between mutation positive and mutation negative cell types within each species, identified using the model‐based analysis of single‐cell transcriptomics algorithm. Gene Ontology enrichment analysis of differentially expressed genes in cardiomyocytes across species revealed alterations in genes involved in muscle development, muscle contraction, muscle hypertrophy, regulation of sarcoplasmic calcium release, ATP metabolic process, and oxidative phosphorylation. Conclusions These common biological processes across species are consistent with known phenotypic aspects of HCM such as hypertrophy, hypercontractility, diastolic dysfunction, and altered energy metabolism. Surprisingly, among conserved biological processes within cardiomyocytes across species, the individual genes driving the biological processes were distinct. This work to identify common and species‐specific disease‐promoting pathway differences will allow development of targeted therapies for both human and veterinary application and will facilitate an understanding of the idiosyncrasies of mouse models. |
| format | Article |
| id | doaj-art-7f0135e0a4884c1981b1ffb8e925f1fc |
| institution | DOAJ |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-7f0135e0a4884c1981b1ffb8e925f1fc2025-08-20T03:07:46ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-01-0114110.1161/JAHA.124.035780Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene ExpressionSamia A. Ali0Gayani Perera1Jason Laird2Rebecca Batorsky3Martin S. Maron4Victor N. Rivas5Joshua A. Stern6Samantha Harris7Michael T. Chin8Tufts Graduate School of Biomedical Sciences Boston MA USAMolecular Cardiology Research Institute, Tufts Medical Center Boston MA USADepartment of Environmental Health and Engineering, Bloomberg School of Public Health Johns Hopkins University Baltimore MD USAData Intensive Studies Center Tufts University Medford MA USAHypertrophic Cardiomyopathy Center Lahey Clinic Burlington MA USADepartment of Clinical Sciences, College of Veterinary Medicine North Carolina State University Raleigh NC USADepartment of Clinical Sciences, College of Veterinary Medicine North Carolina State University Raleigh NC USADepartment of Physiology University of Arizona Tucson AZ USATufts Graduate School of Biomedical Sciences Boston MA USABackground Hypertrophic cardiomyopathy (HCM) is a common heritable heart disease where the most frequently associated mutations occur in the myosin‐binding protein C (MYBPC3) sarcomere‐associated gene. HCM is also a common veterinary clinical problem in certain cat breeds such as Maine Coons and Ragdolls, also most associated with mutations in MYBPC3. Mouse models of HCM in which Mybpc3 mutations are introduced recapitulate some, but not all, features of human HCM. Methods and Results To elucidate the common and distinctive pathological pathways across species and foster a greater understanding of the concordance of mouse HCM models to clinical mybpc3‐associated HCM, we generated single nuclei RNA‐sequencing data sets from feline, human, and murine heart tissue carrying MYBPC3 variants. Numerous genes were differentially expressed between mutation positive and mutation negative cell types within each species, identified using the model‐based analysis of single‐cell transcriptomics algorithm. Gene Ontology enrichment analysis of differentially expressed genes in cardiomyocytes across species revealed alterations in genes involved in muscle development, muscle contraction, muscle hypertrophy, regulation of sarcoplasmic calcium release, ATP metabolic process, and oxidative phosphorylation. Conclusions These common biological processes across species are consistent with known phenotypic aspects of HCM such as hypertrophy, hypercontractility, diastolic dysfunction, and altered energy metabolism. Surprisingly, among conserved biological processes within cardiomyocytes across species, the individual genes driving the biological processes were distinct. This work to identify common and species‐specific disease‐promoting pathway differences will allow development of targeted therapies for both human and veterinary application and will facilitate an understanding of the idiosyncrasies of mouse models.https://www.ahajournals.org/doi/10.1161/JAHA.124.035780differential gene expressionfeline cardiomyopathiesgene ontology enrichment analysishypertrophic cardiomyopathymyosin‐binding protein Csarcomere |
| spellingShingle | Samia A. Ali Gayani Perera Jason Laird Rebecca Batorsky Martin S. Maron Victor N. Rivas Joshua A. Stern Samantha Harris Michael T. Chin Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease differential gene expression feline cardiomyopathies gene ontology enrichment analysis hypertrophic cardiomyopathy myosin‐binding protein C sarcomere |
| title | Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression |
| title_full | Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression |
| title_fullStr | Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression |
| title_full_unstemmed | Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression |
| title_short | Single Cell Transcriptomic Profiling of MYBPC3‐Associated Hypertrophic Cardiomyopathy Across Species Reveals Conservation of Biological Process But Not Gene Expression |
| title_sort | single cell transcriptomic profiling of mybpc3 associated hypertrophic cardiomyopathy across species reveals conservation of biological process but not gene expression |
| topic | differential gene expression feline cardiomyopathies gene ontology enrichment analysis hypertrophic cardiomyopathy myosin‐binding protein C sarcomere |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.035780 |
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