Abstract
Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease.
Highlights
Alternative splicing is a molecular process by which introns are removed from pre-mRNA, while exons are linked together to encode for different protein products in various tissues [1]
Cis-regulatory elements function as enhancers or silencers according to their position and context to recruit trans-regulatory factors, which consist of RNA binding proteins (RBPs) and other splicing factors [7,9]
The exons in PEVK (Proline (P), Glutamate (E), Valine (V), Lysine (K)) and the (K)) and the immunoglobulin-rich region of titin were mis-spliced, which accounts for the immunoglobulin-rich region of titin were mis-spliced, which accounts for the dominant expression dominant expression of the larger titin isoform and sarcomere distensibility in both of the larger titin isoform and sarcomere distensibility in both Rbm20-deficient rats and humans
Summary
Alternative splicing is a molecular process by which introns are removed from pre-mRNA, while exons are linked together to encode for different protein products in various tissues [1]. It is a crucial mechanism for modulating expression of genes in multiple cellular processes and the major contributor to proteomic diversity [2]. Cis-regulatory elements function as enhancers or silencers according to their position and context to recruit trans-regulatory factors, which consist of RNA binding proteins (RBPs) and other splicing factors [7,9]. The mutations cause gain or loss of splicing function and alternation in splicing factors which could trigger the onset of various diseases, for example, heart disease. We will focus on the intersection between muscle-specific alternative splicing and heart disease, with a particular emphasis on a muscle-specific splicing factor RBM20 and its regulatory roles in heart disease
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