The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis
Abstract Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55557-4 |
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| author | Peilu She Bangjun Gao Dongliang Li Chen Wu Xuejiao Zhu Yuan He Fei Mo Yao Qi Daqing Jin Yewei Chen Xin Zhao Jinzhong Lin Hairong Hu Jia Li Bing Zhang Peng Xie Chengqi Lin Vincent M. Christoffels Yueheng Wu Ping Zhu Tao P. Zhong |
| author_facet | Peilu She Bangjun Gao Dongliang Li Chen Wu Xuejiao Zhu Yuan He Fei Mo Yao Qi Daqing Jin Yewei Chen Xin Zhao Jinzhong Lin Hairong Hu Jia Li Bing Zhang Peng Xie Chengqi Lin Vincent M. Christoffels Yueheng Wu Ping Zhu Tao P. Zhong |
| author_sort | Peilu She |
| collection | DOAJ |
| description | Abstract Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function. |
| format | Article |
| id | doaj-art-e0332aba8ab547d08a61fc73e32d69ff |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e0332aba8ab547d08a61fc73e32d69ff2025-01-05T12:40:48ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-024-55557-4The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasisPeilu She0Bangjun Gao1Dongliang Li2Chen Wu3Xuejiao Zhu4Yuan He5Fei Mo6Yao Qi7Daqing Jin8Yewei Chen9Xin Zhao10Jinzhong Lin11Hairong Hu12Jia Li13Bing Zhang14Peng Xie15Chengqi Lin16Vincent M. Christoffels17Yueheng Wu18Ping Zhu19Tao P. Zhong20Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversitySchool of Biological Science and Medical Engineering, Southeast UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversitySchool of Life Sciences, Fudan UniversitySchool of Life Sciences, Fudan UniversitySchool of Life Sciences, Fudan UniversityCenter for Excellence in Brain Science and Intelligence Technology, Chinese Academy of SciencesShanghai Center for Systems Biomedicine, School of Medicine, Shanghai Jiao Tong UniversitySchool of Biological Science and Medical Engineering, Southeast UniversitySchool of Biological Science and Medical Engineering, Southeast UniversityDepartment of Medical Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of AmsterdamGuangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityGuangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityAbstract Energy deprivation and metabolic rewiring of cardiomyocytes are widely recognized hallmarks of heart failure. Here, we report that HEY2 (a Hairy/Enhancer-of-split-related transcriptional repressor) is upregulated in hearts of patients with dilated cardiomyopathy. Induced Hey2 expression in zebrafish hearts or mammalian cardiomyocytes impairs mitochondrial respiration, accompanied by elevated ROS, resulting in cardiomyocyte apoptosis and heart failure. Conversely, Hey2 depletion in adult mouse hearts and zebrafish enhances the expression of mitochondrial oxidation genes and cardiac function. Multifaceted genome-wide analyses reveal that HEY2 enriches at the promoters of genes known to regulate metabolism (including Ppargc1, Esrra and Cpt1) and colocalizes with HDAC1 to effectuate histone deacetylation and transcriptional repression. Consequently, restoration of PPARGC1A/ESRRA in Hey2- overexpressing zebrafish hearts or human cardiomyocyte-like cells rescues deficits in mitochondrial bioenergetics. Knockdown of Hey2 in adult mouse hearts protects against doxorubicin-induced cardiac dysfunction. These studies reveal an evolutionarily conserved HEY2/HDAC1-Ppargc1/Cpt transcriptional module that controls energy metabolism to preserve cardiac function.https://doi.org/10.1038/s41467-024-55557-4 |
| spellingShingle | Peilu She Bangjun Gao Dongliang Li Chen Wu Xuejiao Zhu Yuan He Fei Mo Yao Qi Daqing Jin Yewei Chen Xin Zhao Jinzhong Lin Hairong Hu Jia Li Bing Zhang Peng Xie Chengqi Lin Vincent M. Christoffels Yueheng Wu Ping Zhu Tao P. Zhong The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis Nature Communications |
| title | The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis |
| title_full | The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis |
| title_fullStr | The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis |
| title_full_unstemmed | The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis |
| title_short | The transcriptional repressor HEY2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis |
| title_sort | transcriptional repressor hey2 regulates mitochondrial oxidative respiration to maintain cardiac homeostasis |
| url | https://doi.org/10.1038/s41467-024-55557-4 |
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