RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional Manner
Abstract Stimulating cardiomyocyte (CM) dedifferentiation and cell cycle activity (DACCA) is essential for triggering daughter CM formation. In addition to transcriptional processes, RNA‐binding proteins (RBPs) are emerging as crucial post‐transcriptional players in regulating CM DACCA. However, whe...
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202402371 |
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| author | Chuling Li Yijin Chen Qiqi Chen Haoxiang Huang Michael Hesse Yilin Zhou Ming Jin Yu Liu Yifei Ruan Xiang He Guoquan Wei Hao Zheng Senlin Huang Guojun Chen Wangjun Liao Yulin Liao Yanmei Chen Jianping Bin |
| author_facet | Chuling Li Yijin Chen Qiqi Chen Haoxiang Huang Michael Hesse Yilin Zhou Ming Jin Yu Liu Yifei Ruan Xiang He Guoquan Wei Hao Zheng Senlin Huang Guojun Chen Wangjun Liao Yulin Liao Yanmei Chen Jianping Bin |
| author_sort | Chuling Li |
| collection | DOAJ |
| description | Abstract Stimulating cardiomyocyte (CM) dedifferentiation and cell cycle activity (DACCA) is essential for triggering daughter CM formation. In addition to transcriptional processes, RNA‐binding proteins (RBPs) are emerging as crucial post‐transcriptional players in regulating CM DACCA. However, whether post‐transcriptional regulation of CM DACCA by RBPs could effectively trigger daughter CM formation remains unknown. By performing integrated bioinformatic analysis of snRNA‐seq data from neonatal and adult hearts, this study identified Hnrnpa1 as a potential RBP regulating CM DACCA. Hnrnpa1 expression decreased significantly during postnatal heart development. With the use of α‐MHC‐H2B‐mCh/CAG‐eGFP‐anillin transgenic mice, Hnrnpa1 overexpression promoted CM DACCA, thereby triggering daughter CM formation and enhancing cardiac repair after myocardial infarction (MI). In contrast, CRISPR/Cas9 technology is used to generate CM‐specific Hnrnpa1 knockout mice. Hnrnpa1 knockout inhibited cardiac regeneration and worsened cardiac function in the neonatal MI model. Nanopore RNA sequencing, RIP assay, IP‐MS, MeRIP‐qPCR, PAR‐CLIP and luciferase reporter experiments showed that Hnrnpa1 induced Mettl3 post‐transcriptional splicing to inhibit m6A‐dependent Pbx1 and E2F1 degradation, thereby increasing Runx1, Ccne1, Cdk2 and Ccnb2 expression to promote CM DACCA. In conclusion, Hnrnpa1 triggered daughter CM formation by promoting CM DACCA in a post‐transcriptional manner, indicating that Hnrnpa1 might serve as a promising target in cardiac repair post‐MI. |
| format | Article |
| id | doaj-art-81316a69a1e94d8b9a810d99f57328af |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-81316a69a1e94d8b9a810d99f57328af2025-01-13T15:29:43ZengWileyAdvanced Science2198-38442025-01-01122n/an/a10.1002/advs.202402371RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional MannerChuling Li0Yijin Chen1Qiqi Chen2Haoxiang Huang3Michael Hesse4Yilin Zhou5Ming Jin6Yu Liu7Yifei Ruan8Xiang He9Guoquan Wei10Hao Zheng11Senlin Huang12Guojun Chen13Wangjun Liao14Yulin Liao15Yanmei Chen16Jianping Bin17Department of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaInstitute of Physiology I, Life and Brain Center Medical Faculty University of Bonn 53115 Bonn GermanyDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Oncology Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaDepartment of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University Guangzhou 510515 ChinaAbstract Stimulating cardiomyocyte (CM) dedifferentiation and cell cycle activity (DACCA) is essential for triggering daughter CM formation. In addition to transcriptional processes, RNA‐binding proteins (RBPs) are emerging as crucial post‐transcriptional players in regulating CM DACCA. However, whether post‐transcriptional regulation of CM DACCA by RBPs could effectively trigger daughter CM formation remains unknown. By performing integrated bioinformatic analysis of snRNA‐seq data from neonatal and adult hearts, this study identified Hnrnpa1 as a potential RBP regulating CM DACCA. Hnrnpa1 expression decreased significantly during postnatal heart development. With the use of α‐MHC‐H2B‐mCh/CAG‐eGFP‐anillin transgenic mice, Hnrnpa1 overexpression promoted CM DACCA, thereby triggering daughter CM formation and enhancing cardiac repair after myocardial infarction (MI). In contrast, CRISPR/Cas9 technology is used to generate CM‐specific Hnrnpa1 knockout mice. Hnrnpa1 knockout inhibited cardiac regeneration and worsened cardiac function in the neonatal MI model. Nanopore RNA sequencing, RIP assay, IP‐MS, MeRIP‐qPCR, PAR‐CLIP and luciferase reporter experiments showed that Hnrnpa1 induced Mettl3 post‐transcriptional splicing to inhibit m6A‐dependent Pbx1 and E2F1 degradation, thereby increasing Runx1, Ccne1, Cdk2 and Ccnb2 expression to promote CM DACCA. In conclusion, Hnrnpa1 triggered daughter CM formation by promoting CM DACCA in a post‐transcriptional manner, indicating that Hnrnpa1 might serve as a promising target in cardiac repair post‐MI.https://doi.org/10.1002/advs.202402371daughter cardiomyocyte formationdedifferentiation and cell cycle activityHnrnpa1post‐transcriptional regulationRNA‐binding protein |
| spellingShingle | Chuling Li Yijin Chen Qiqi Chen Haoxiang Huang Michael Hesse Yilin Zhou Ming Jin Yu Liu Yifei Ruan Xiang He Guoquan Wei Hao Zheng Senlin Huang Guojun Chen Wangjun Liao Yulin Liao Yanmei Chen Jianping Bin RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional Manner Advanced Science daughter cardiomyocyte formation dedifferentiation and cell cycle activity Hnrnpa1 post‐transcriptional regulation RNA‐binding protein |
| title | RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional Manner |
| title_full | RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional Manner |
| title_fullStr | RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional Manner |
| title_full_unstemmed | RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional Manner |
| title_short | RNA‐Binding Protein Hnrnpa1 Triggers Daughter Cardiomyocyte Formation by Promoting Cardiomyocyte Dedifferentiation and Cell Cycle Activity in a Post‐Transcriptional Manner |
| title_sort | rna binding protein hnrnpa1 triggers daughter cardiomyocyte formation by promoting cardiomyocyte dedifferentiation and cell cycle activity in a post transcriptional manner |
| topic | daughter cardiomyocyte formation dedifferentiation and cell cycle activity Hnrnpa1 post‐transcriptional regulation RNA‐binding protein |
| url | https://doi.org/10.1002/advs.202402371 |
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