Abstract
Alternative splicing is a regulatory mechanism essential for cell differentiation and tissue organization. More than 90% of human genes are regulated by alternative splicing events, which participate in cell fate determination. The general mechanisms of splicing events are well known, whereas only recently have deep-sequencing, high throughput analyses and animal models provided novel information on the network of functionally coordinated, tissue-specific, alternatively spliced exons. Heart development and cardiac tissue differentiation require thoroughly regulated splicing events. The ribonucleoprotein RBM20 is a key regulator of the alternative splicing events required for functional and structural heart properties, such as the expression of TTN isoforms. Recently, the polypyrimidine tract-binding protein PTBP1 has been demonstrated to participate with RBM20 in regulating splicing events. In this review, we summarize the updated knowledge relative to RBM20 and PTBP1 structure and molecular function; their role in alternative splicing mechanisms involved in the heart development and function; RBM20 mutations associated with idiopathic dilated cardiovascular disease (DCM); and the consequences of RBM20-altered expression or dysfunction. Furthermore, we discuss the possible application of targeting RBM20 in new approaches in heart therapies.
Highlights
Splicing is a general mechanism that allows the removal of intron sequences from a precursor to mature mRNA
We recently investigated the involvement of RBM20 and polypyrimidine-tract binding protein 1 (PTBP1) in the regulation of the alternative splicing of the formin homology 2 domain containing 3 (FHOD3) protein, an RNA-seq-predicted
We found that both RBM20 and PTBP1 influence the balance of the formin homology domain containing 3 (FHOD3) splicing pattern, promoting the skipping of exons 12, 13 and 14 (Figure 2c)
Summary
Splicing is a general mechanism that allows the removal of intron sequences from a precursor to mature mRNA. The mechanism that allows alternative splicing has been intensively studied and several bioinformatics tools have been developed to predict the transcript variants of a specific gene [2,3]. Intensive studies have contributed to identify several specific factors that participate in heart development as well as their involvement in heart diseases. Most of these factors, including transcription factors, constitutive proteins that accounts for cytoskeleton organization, electric impulse transmission, channel and cell-to-cell connection are regulated by alternative splicing [24,25]. We review the current knowledge about the contribution of RBM20 and PTBP1 in heart alternative splicing events, their combinatory role in selecting specific exons and RBM20’s role in cardiovascular diseases
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