RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy

doi:10.1007/s13238-018-0578-8

Protein Cell

2019, Vol. 10

Issue (6) : 405-416 https://doi.org/10.1007/s13238-018-0578-8

RESEARCH ARTICLE

RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy

Jing Liu¹, Xu Kong¹, Mengkai Zhang¹, Xiao Yang², Xiuqin Xu¹(

)

¹. The Institute of Stem Cell and Regenerative Medicine, Medical College, Xiamen University, Xiamen 361100, China
². State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, China

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Abstract

RNA splicing contributes to a broad spectrum of posttranscriptional 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.

Keywords RNA binding protein RBM24 dilated cardiomyopathy alternative splicing heart failure

Corresponding Author(s): Xiuqin Xu

Issue Date: 19 June 2019

Cite this article:

Jing Liu,Xu Kong,Mengkai Zhang, et al. RNA binding protein 24 deletion disrupts global alternative splicing and causes dilated cardiomyopathy[J]. Protein Cell, 2019, 10(6): 405-416.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-018-0578-8
https://academic.hep.com.cn/pac/EN/Y2019/V10/I6/405

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