RNA Splicing

Abstract

RNA splicing, a post-transcriptional process necessary to form a mature mRNA, was discovered in the late 1970s. 1 Two different modes of splicing have been defined, that is, constitutive splicing and alternative splicing. Constitutive splicing is the process of removing introns from the premRNA, and joining the exons together to form a mature mRNA. Alternative splicing, on the other hand, is the process where exons can be included or excluded in different combinations to create a diverse array of mRNA transcripts from a single pre-mRNA and therefore serves as a process to increase the diversity of the transcriptome. The estimated number of alternative splicing events in the human transcriptome has risen sharply over the past decades. In the 1980s, it was thought that about 5% of human genes were subjected to alternative splicing.2 In 2002, this number had risen to 60%, 3 and now, after implementation of next-generation-sequencing technologies, we know that the vast majority, >95% of mRNAs, are subjected to alternative splicing. 4 Nevertheless, the function of a large fraction of these splice isoforms remains to be elucidated. Furthermore, it is anticipated that in different tissues, or in tissues with different disease states, new isoforms still remain to be identified. 5The process of splicing is highly conserved during evolution. Splicing is more prevalent in multicellular than in unicellular eukaryotes because of the lower number of introncontaining genes in the latter. 6 Later in evolution, alternative splicing becomes more prevalent in vertebrates than in invertebrates. Interestingly, just a single exon-skipping event in the RNA-binding protein (RBP), polypyrimidine tract binding protein 1 has been shown to direct numerous alternative splicing changes between species, indicating that a single splicing event can amplify transcriptome diversity between species. 7The recent observation that the total number of protein-coding genes does not differ much between species, fueled the hypothesis that alternative splicing largely contributes to organism diversity. And indeed, as we move up the phylogenetic tree, alternative splicing complexity increases, with the highest complexity in primates. 8,9The aim of this review is to give a comprehensive overview of all aspects of constitutive and alternative splicing and their regulators, as well as the importance of these different aspects in human disease, with a focus on the heart. In addition, we discuss possible therapeutic interventions and try to uncover potential future directions of research. Major and Minor SpliceosomeRNA splicing is performed by the spliceosome, a large and dynamic ribonucleoprotein complex composed of proteins and small nuclear RNAs (snRNAs), which assembles on the pre-mRNA (Figure 1). Ribonucleoproteins consist of 1 or 2 small nuclear RNAs (snRNAs; U1, U2, U4/U6, or U5), and a variable number of complex-specific proteins.

A Loss of Function Screen of Epigenetic Modifiers and Splicing Factors during Early Stage of Cardiac Reprogramming

“…RNA splicing is increasingly being recognized as an important layer of posttranslational gene regulation in the heart [ 29 ]. For instance, splicing factor Sf3b1, a component of U2 snRNPS involved in both constitutive and alternative splicing, is dysregulated in human and mouse models of pathological cardiac hypertrophy [ 30 ].…”

LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies

“…Deletion of ASF/SF2 leads to missplicing of several gene products, including Ca 2+ /calmodulin-dependent protein kinase (CamkIIδ), cardiac troponin T (cTnT), and LIM-domain binding 3 (LDB3). Missplicing of CamkIIδ in ASF/SF2 knockout hearts results in disturbed Ca 2+ handling and severe excitation–contraction coupling defects, leading to dilated cardiomyopathy (DCM) [94,95]. SR-rich splicing factor 2 (SRSF2 or SC35) is another ubiquitously expressed SR protein whose systemic deletion in mice results in embryonic lethality before the onset of cardiogenesis.…”

“…The splicing of four key sarcomeric genes, troponin T2 ( TNNT2 ), TNNI3 , MYH7 , and FLNC were significantly altered in human ischemic cardiomyopathy, DCM, and aortic stenosis [101]. Until now, there have only been a few examples of mutations in the splice sites themselves that are shown to directly cause human heart diseases [95]. One of the first splice site mutations that has been reported to result in heart disease is a G>A point mutation that disrupts the 5′ splice site of exon 15 of cardiac TNNT2 gene and leads to truncated mRNA variants.…”

SF3B1 mutation is a poor prognostic indicator in luminal B and progesterone receptor-negative breast cancer patients

“…The precise excision of introns from precursor mRNAs in eukaryotes is performed by the spliceosome [ 1 ], a macromolecule composed of small nuclear RNAs associated with proteins [ 2 ]. RNA splicing, which includes constitutive and alternative splicing, is a post-transcriptional process necessary to produce mature RNA [ 3 ]. Constitutive splicing is the process of removing introns from pre-mRNA, whereas alternative splicing is the process of including or excluding exons in different combinations to create a diverse array of mRNA transcripts from a single pre-mRNA fragment.…”