Sequencing of mRNA identifies re-expression of fetal splice variants in cardiac hypertrophy

Ames, Elizabeth G.; Lawson, Michael J.; Mackey, Amanda J.; Holmes, Jeffrey W.

doi:10.1016/j.yjmcc.2013.05.004

Cited by 35 publications

(29 citation statements)

References 59 publications

(75 reference statements)

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“…Intriguingly, much like reactivation of selected fetal genes, some fetal splice isoforms are also re-expressed in the stressed or diseased heart. 70 For example, splicing of the sarcomeric proteins titin and myomesin is regulated during development, and their fetal isoforms are re-expressed in the stressed heart. 71 Apart from the re-expression of fetal isoforms, it is known that alternative splicing is broadly altered in cardiac hypertrophy and disease.…”

Section: Alternative Splicing In Diseasementioning

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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Section: Alternative Splicing In Diseasementioning

confidence: 99%

RNA Splicing

Hoogenhof

Pinto

Creemers

2016

Circulation Research

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“…Global alternative splicing profiling has been done in the diseased heart, including cardiac hypertrophy and heart failure. 34,35 For example, an earlier study compared pressure overload-induced cardiac hypertrophy and heart failure in the mouse heart using deep RNA-sequencing and revealed a global change of alternative splicing in the failing murine heart. 35 More recently, Ames et al and other groups also identified a significant number of alternative splicing events during cardiac hypertrophy in rats.…”

Section: Alternative Rna Splicing In Transcriptome Regulationmentioning

confidence: 99%

“…35 More recently, Ames et al and other groups also identified a significant number of alternative splicing events during cardiac hypertrophy in rats. 34,36 For splicing regulators, it is suggested that the expression of PTB and ASF/SF2 is altered in the pressure overload-induced hypertrophic heart. 37 The transcriptome signature and RNA splicing events have also been profiled in human heart disease.…”

Section: Alternative Rna Splicing In Transcriptome Regulationmentioning

confidence: 99%

Transcriptome Complexity in Cardiac Development and Diseases

Gao

Wang

2014

Circ J

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With the advancement of transcriptome profiling by micro-arrays and high-throughput RNA-sequencing, transcriptome complexity and its dynamics are revealed at different levels in cardiovascular development and diseases. In this review, we will highlight the recent progress in our knowledge of cardiovascular transcriptome complexity contributed by RNA splicing, RNA editing and noncoding RNAs. The emerging importance of many of these previously under-explored aspects of gene regulation in cardiovascular development and pathology will be discussed.

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“…While physiological hypertrophy leads to an improvement in life quality by increasing oxygenation capacity and maximal cardiac output, pathological hypertrophy leads to a progressive deterioration of cardiac function ending with fatal heart failure (Song et al 2012 ). RNA-seq was also recently applied to show that the developmental AS program is recapitulated during pressure-overload cardiac hypertrophy in rats ( Ames et al 2013 ). The comparison of AS events in hypertrophy and during heart development revealed a signifi cant overlap, suggesting that hypertrophic hearts reuse some of the regulatory mechanisms involved in normal development (Ames et al 2013 ).…”

mentioning

confidence: 99%

“…RNA-seq was also recently applied to show that the developmental AS program is recapitulated during pressure-overload cardiac hypertrophy in rats ( Ames et al 2013 ). The comparison of AS events in hypertrophy and during heart development revealed a signifi cant overlap, suggesting that hypertrophic hearts reuse some of the regulatory mechanisms involved in normal development (Ames et al 2013 ).…”

mentioning

confidence: 99%

RNA-Binding Proteins in Heart Development

Giudice

Cooper

2014

Advances in Experimental Medicine and Biology

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RNA-binding proteins (RBPs) are key players of posttranscriptional regulation occurring during normal tissue development. All tissues examined thus far have revealed the importance of RBPs in the regulation of complex networks involved in organ morphogenesis, maturation, and function. They are responsible for controlling tissue-specific gene expression by regulating alternative splicing, mRNA stability, translation, and poly-adenylation. The heart is the first organ form during embryonic development and is also the first to acquire functionality. Numerous remodeling processes take place during late cardiac development since fetal heart first adapts to birth and then undergoes a transition to adult functionality. This physiological remodeling involves transcriptional and posttranscriptional networks that are regulated by RBPs. Disruption of the normal regulatory networks has been shown to cause cardiomyopathy in humans and animal models. Here we review the complexity of late heart development and the current information regarding how RBPs control aspects of postnatal heart development. We also review how activities of RBPs are modulated adding complexity to the regulation of developmental networks.

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Sequencing of mRNA identifies re-expression of fetal splice variants in cardiac hypertrophy

Cited by 35 publications

References 59 publications

RNA Splicing

RNA Splicing

Transcriptome Complexity in Cardiac Development and Diseases

RNA-Binding Proteins in Heart Development

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