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

Jing Liu,Xiuqin Xu,Xu Kong,Mengkai Zhang,Xiao Yang

doi:10.1007/s13238-018-0578-8

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.

Highlights

Mammalian genomes encode for a large number of RNA binding proteins (RBPs), which play an important role on post-transcriptional regulation occurring during development and disease
dilated cardiomyopathy (DCM) causative mutations have been detected in almost 50 genes so far, most of the genetic studies are focused on genes involved in the sarcomere organization that are important for heart contraction, such as TTN, TPM1, MYH7 and TNNT2 (Tayal et al, 2017)
We have previously reported that RNA binding motif protein 24 (RBM24) was enriched in human embryonic stem cells (ESCs)-derived cardiomyocytes and highly expressed in human and mouse heart (Xu et al, 2008; Xu et al, 2009)

Summary

Introduction

Mammalian genomes encode for a large number of RNA binding proteins (RBPs), which play an important role on post-transcriptional regulation occurring during development and disease. AS regulation differentially produces structurally and functionally distinct messenger RNA (mRNA) and protein isoforms, provides a powerful additional mechanism with which to control cell fate and physiological response (Cooper, 2005; Kalsotra and Cooper, 2011). Cardiomyopathy ranks among the most prevalent causes of premature death in the world. Among these primary cardiomyopathies, the most common form is dilated cardiomyopathy (DCM) (Tayal et al, 2017). DCM causative mutations have been detected in almost 50 genes so far, most of the genetic studies are focused on genes involved in the sarcomere organization that are important for heart contraction, such as TTN, TPM1, MYH7 and TNNT2 (Tayal et al, 2017)

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Results

Conclusion