RBM24 Is a Major Regulator of Muscle-Specific Alternative Splicing

Yang, Jiwen; Hung, Lee-Hsueh; Licht, Thomas; Kostin, Sawa; Looso, Mario; Khrameeva, Ekaterina E.; Bindereif, Albrecht; Schneider, André; Braun, Thomas

doi:10.1016/j.devcel.2014.08.025

Cited by 129 publications

(210 citation statements)

References 44 publications

(57 reference statements)

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“…The function of the ECC and sarcomere is sensitive to the aberrant expression of structural components or altered cellular environments, and changes of ECC and sarcomere contraction lead to heart malfunction and disease (48). A number of splicing factors have been shown to be required for normal heart development and function (11,(13)(14)(15)(16). They include both general and tissue-specific splicing factors.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the Titin gene is one of the major targets of RBM20 (11,12). On the other hand, loss of RBM24 expression gives rise to many exon skipping events (13), implicating RBM24 as a splicing activator. Strikingly, there is little overlap between RBM20 and RBM24 splicing targets, suggesting that RBM20 and RBM24 are involved in regulating splicing of distinct groups of pre-mRNAs and there is little cross-talk between these two splicing factors.…”

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confidence: 99%

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hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

Beetz

O’Keeffe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

118

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We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation-contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation-contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing.T he expression of more than 95% of human genes is affected by alternative pre-mRNA splicing (AS) (1, 2). Differentially spliced isoforms play distinct roles in a temporally and spatially specific manner (3), and mutations that lead to aberrant splicing are the cause of many human genetic diseases (4). RNA-binding proteins (RBPs) play a central role in the regulation of alternative splicing during development and disease. They function primarily by positively or negatively regulating splice-site recognition by the spliceosome (1). Many RBPs are expressed in specific tissues, and AS is regulated by the combinatorial activities of these factors on specific pre-mRNAs through their interactions with distinct regulatory sequences in premRNA that function as splicing enhancers or silencers (5).The developing heart is one of the best studied systems where splicing changes occur during normal development, and mutations affecting specific splicing outcomes contribute to cardiomyopathy (6, 7). Although these mutations can either disrupt splicing elements or affect the expression of specific splicing factors, the latter mechanism is clearly responsible for the distinct splicing profiles at different developmental stages. For example, the dynamics of alternative splicing during postnatal heart development correlate with expression changes of many RBPs, including CUG-BP, Elavlike family member 1 (CELF1), Muscleblind-like 1 (MBNL1), and FOX proteins (8). Detailed biochemical studies have elucidated the mechanisms by which these splicing factors regulate splicing in a position-and context-dependent manner (9, 10). The function of other RBPs during heart development has also been studied. For example, two of the muscle-specific splicing factors, RBM20 and RBM24, play distinct roles in splicing regulation. RBM20 mainly acts as a splicing repressor, as its absence leads to multiple exon inclusion events in the heart. For example, the Titin gene is one of...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

Beetz

O’Keeffe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

118

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“…56 Mice lacking Rbm24 die between E12.5 and E14.5 because of multiple cardiac malformations, including ventricular septum defects, reduced trabeculation and compaction, and dilated atria. Strikingly, sarcomerogenesis was almost completely abolished in knockout embryos.…”

Section: Splicing Factors In the Developing Heartmentioning

confidence: 99%

“…Several mouse models in which a splicing factor has been knocked out (eg, Rbm24, SC35, SRp20, and SRp38) support this idea. 56,57,60,79 Also, before the upcoming of nextgeneration sequencing, the search for candidate genes used to be hypothesis driven and often did not include splice factors, and consequently, genes encoding splice factors were simply not sequenced in affected patients. It has only recently become possible to look for candidate genes in a broader and often unbiased way, and splicing-related genes can be sequenced on a larger scale.…”

Section: Splice Factors In the Diseased Heartmentioning

confidence: 99%

RNA Splicing

Hoogenhof

Pinto

Creemers

2016

Circulation Research

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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.

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“…A few examples are: Nova, an RNA-binding protein that specifically regulates AS of several proteins involved in neuronal synapses 18 ; ESRP1 and -2, epithelial splicing regulatory proteins 1 and 2 that are thought to be crucial in defining the epithelial state of a cell by coordinating the exon content of hundreds of transcripts 19,20 ; and Rbm24 and RbFox1, RNA-binding proteins that control muscle-specific AS. 21 This raises the possibility that kidney development and/or function may also have a yet uncharacterized master splice factor.…”

Section: Regulation Of As By Splice Factors and Intronic/exonic Elementsmentioning

confidence: 99%

Alternative Splicing in CKD

Stevens

Oltean

2016

JASN

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Alternative splicing (AS) has emerged in the postgenomic era as one of the main drivers of proteome diversity, with $94% of multiexon genes alternatively spliced in humans. AS is therefore one of the main control mechanisms for cell phenotype, and is a process deregulated in disease. Numerous reports describe pathogenic mutations in splice factors, splice sites, or regulatory sequences. Additionally, compared with the physiologic state, disease often associates with an abnormal proportion of splice isoforms (or novel isoforms), without an apparent driver mutation. It is therefore essential to study how AS is regulated in physiology, how it contributes to pathogenesis, and whether we can manipulate faulty splicing for therapeutic advantage. Although the disease most commonly linked to deregulation of AS in several genes is cancer, many reports detail pathogenic splice variants in diseases ranging from neuromuscular disorders to diabetes or cardiomyopathies. A plethora of splice variants have been implicated in CKDs as well. In this review, we describe examples of these CKD-associated splice variants and ideas on how to manipulate them for therapeutic benefit.

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RBM24 Is a Major Regulator of Muscle-Specific Alternative Splicing

Cited by 129 publications

References 44 publications

hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function

RNA Splicing

Alternative Splicing in CKD

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