RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy
Abstract RNA splicing contributes to a broad spectrum of post-transcriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RB...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2018-09-01
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| Series: | Protein & Cell |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1007/s13238-018-0578-8 |
| _version_ | 1797764022982934528 |
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| author | Jing Liu Xu Kong Mengkai Zhang Xiao Yang Xiuqin Xu |
| author_facet | Jing Liu Xu Kong Mengkai Zhang Xiao Yang Xiuqin Xu |
| author_sort | Jing Liu |
| collection | DOAJ |
| description | Abstract RNA splicing contributes to a broad spectrum of post-transcriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM. |
| first_indexed | 2024-03-12T19:50:46Z |
| format | Article |
| id | doaj.art-1fe40c402df144789e2d9f59b02caf07 |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T19:50:46Z |
| publishDate | 2018-09-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-1fe40c402df144789e2d9f59b02caf072023-08-02T03:11:32ZengOxford University PressProtein & Cell1674-800X1674-80182018-09-0110640541610.1007/s13238-018-0578-8RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathyJing Liu0Xu Kong1Mengkai Zhang2Xiao Yang3Xiuqin Xu4The Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen UniversityThe Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen UniversityThe Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen UniversityState Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of BiotechnologyThe Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen UniversityAbstract RNA splicing contributes to a broad spectrum of post-transcriptional gene regulation during normal development, as well as pathological manifestation of heart diseases. However, the functional role and regulation of splicing in heart failure remain poorly understood. RNA binding protein (RBP), a major component of the splicing machinery, is a critical factor in this process. RNA binding motif protein 24 (RBM24) is a tissue-specific RBP which is highly expressed in human and mouse heart. Previous studies demonstrated the functional role of RBM24 in the embryonic heart development. However, the role of RBM24 in postnatal heart development and heart disease has not been investigated. In this paper, using conditional RBM24 knockout mice, we demonstrated that ablation of RBM24 in postnatal heart led to rapidly progressive dilated cardiomyopathy (DCM), heart failure, and postnatal lethality. Global splicing profiling revealed that RBM24 regulated a network of genes related to cardiac function and diseases. Knockout of RBM24 resulted in misregulation of these splicing transitions which contributed to the subsequent development of cardiomyopathy. Notably, our analysis identified RBM24 as a splice factor that determined the splicing switch of a subset of genes in the sacomeric Z-disc complex, including Titin, the major disease gene of DCM and heart failure. Together, this study identifies regulation of RNA splicing by RBM24 as a potent player in remodeling of heart during postnatal development, and provides novel mechanistic insights to the pathogenesis of DCM.http://link.springer.com/article/10.1007/s13238-018-0578-8RNA binding proteinRBM24dilated cardiomyopathyalternative splicingheart failure |
| spellingShingle | Jing Liu Xu Kong Mengkai Zhang Xiao Yang Xiuqin Xu RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy Protein & Cell RNA binding protein RBM24 dilated cardiomyopathy alternative splicing heart failure |
| title | RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy |
| title_full | RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy |
| title_fullStr | RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy |
| title_full_unstemmed | RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy |
| title_short | RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy |
| title_sort | rna binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy |
| topic | RNA binding protein RBM24 dilated cardiomyopathy alternative splicing heart failure |
| url | http://link.springer.com/article/10.1007/s13238-018-0578-8 |
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