Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice
Heart failure (HF) is a major global health challenge, contributing to over 18 million deaths annually. While the roles of genetic and environmental factors are widely studied, the role of DNA methylation in HF pathogenesis is not fully understood. This study leverages the Hybrid Mouse Diversity Pan...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Epigenetics |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15592294.2025.2524411 |
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| author | Caitlin Lahue Eleanor Wong Aryan Dalal Wilson Tan Lek Wen Shuxun Ren Roger Foo Yibin Wang Christoph D. Rau |
| author_facet | Caitlin Lahue Eleanor Wong Aryan Dalal Wilson Tan Lek Wen Shuxun Ren Roger Foo Yibin Wang Christoph D. Rau |
| author_sort | Caitlin Lahue |
| collection | DOAJ |
| description | Heart failure (HF) is a major global health challenge, contributing to over 18 million deaths annually. While the roles of genetic and environmental factors are widely studied, the role of DNA methylation in HF pathogenesis is not fully understood. This study leverages the Hybrid Mouse Diversity Panel (HMDP) to investigate the relationship between DNA methylation, gene expression, and HF phenotypes under isoproterenol-induced cardiac stress. Using reduced representational bisulfite sequencing, we analyzed DNA methylation profiles in the left ventricles of 90 HMDP strains. Epigenome-wide association studies identified 56 CpG loci linked to HF phenotypes, with 18 loci predicting HF progression. Key genes, including Prkag2, Anks1a, and Mospd3, were implicated through integration with gene expression and phenotypic data. In vitro validation confirmed the roles of Anks1aand Mospd3 in attenuating isoproterenol-induced hypertrophy. Additionally, treatment with the DNA methyltransferase inhibitor RG108 mitigated cardiac hypertrophy, preserved ejection fraction, and restored methylation-sensitive gene expression, underscoring the therapeutic potential of targeting DNA methylation in HF. This study highlights the interplay between DNA methylation, gene expression, and HF progression, offering new insights into its molecular underpinnings. The findings emphasize the role of epigenetic regulation in HF and suggest DNA methylation as a promising target for therapeutic intervention. |
| format | Article |
| id | doaj-art-e186221d4c504c3cb69886986a3fcf4a |
| institution | Kabale University |
| issn | 1559-2294 1559-2308 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj-art-e186221d4c504c3cb69886986a3fcf4a2025-08-20T03:28:10ZengTaylor & Francis GroupEpigenetics1559-22941559-23082025-12-0120110.1080/15592294.2025.2524411Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of miceCaitlin Lahue0Eleanor Wong1Aryan Dalal2Wilson Tan Lek Wen3Shuxun Ren4Roger Foo5Yibin Wang6Christoph D. Rau7Department of Genetics and Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAGenome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), SingaporeDepartment of Genetics and Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAGenome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), SingaporeDuke-NUS Medical School, Signature Research Program in Cardiovascular and Metabolic Diseases, SingaporeGenome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), SingaporeDuke-NUS Medical School, Signature Research Program in Cardiovascular and Metabolic Diseases, SingaporeDepartment of Genetics and Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, USAHeart failure (HF) is a major global health challenge, contributing to over 18 million deaths annually. While the roles of genetic and environmental factors are widely studied, the role of DNA methylation in HF pathogenesis is not fully understood. This study leverages the Hybrid Mouse Diversity Panel (HMDP) to investigate the relationship between DNA methylation, gene expression, and HF phenotypes under isoproterenol-induced cardiac stress. Using reduced representational bisulfite sequencing, we analyzed DNA methylation profiles in the left ventricles of 90 HMDP strains. Epigenome-wide association studies identified 56 CpG loci linked to HF phenotypes, with 18 loci predicting HF progression. Key genes, including Prkag2, Anks1a, and Mospd3, were implicated through integration with gene expression and phenotypic data. In vitro validation confirmed the roles of Anks1aand Mospd3 in attenuating isoproterenol-induced hypertrophy. Additionally, treatment with the DNA methyltransferase inhibitor RG108 mitigated cardiac hypertrophy, preserved ejection fraction, and restored methylation-sensitive gene expression, underscoring the therapeutic potential of targeting DNA methylation in HF. This study highlights the interplay between DNA methylation, gene expression, and HF progression, offering new insights into its molecular underpinnings. The findings emphasize the role of epigenetic regulation in HF and suggest DNA methylation as a promising target for therapeutic intervention.https://www.tandfonline.com/doi/10.1080/15592294.2025.2524411Heart failureDNA methylationepigenome-wide association studyhybrid mouse diversity panelcardiac hypertrophyisoproterenol |
| spellingShingle | Caitlin Lahue Eleanor Wong Aryan Dalal Wilson Tan Lek Wen Shuxun Ren Roger Foo Yibin Wang Christoph D. Rau Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice Epigenetics Heart failure DNA methylation epigenome-wide association study hybrid mouse diversity panel cardiac hypertrophy isoproterenol |
| title | Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice |
| title_full | Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice |
| title_fullStr | Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice |
| title_full_unstemmed | Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice |
| title_short | Mapping DNA methylation to cardiac pathologies induced by beta-adrenergic stimulation in a large panel of mice |
| title_sort | mapping dna methylation to cardiac pathologies induced by beta adrenergic stimulation in a large panel of mice |
| topic | Heart failure DNA methylation epigenome-wide association study hybrid mouse diversity panel cardiac hypertrophy isoproterenol |
| url | https://www.tandfonline.com/doi/10.1080/15592294.2025.2524411 |
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