RNA-Binding Proteins: Splicing Factors and Disease

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Abstract

Pre-mRNA splicing is mediated by interactions of the Core Spliceosome and an array of accessory RNA binding proteins with cis-sequence elements. Splicing is a major regulatory component in higher eukaryotes. Disruptions in splicing are a major contributor to human disease. One in three hereditary disease alleles are believed to cause aberrant splicing. Hereditary disease alleles can alter splicing by disrupting a splicing element, creating a toxic RNA, or affecting splicing factors. One of the challenges of medical genetics is identifying causal variants from the thousands of possibilities discovered in a clinical sequencing experiment. Here we review the basic biochemistry of splicing, the mechanisms of splicing mutations, the methods for identifying splicing mutants, and the potential of therapeutic interventions.

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Most cited references 66

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HITS-CLIP yields genome-wide insights into brain alternative RNA processing

Donny D. Licatalosi, Aldo Mele, John Fak … (2008)

Summary Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3′ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

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RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.

Wei. Guo, Sebastian Schafer, Marion L. Greaser … (2012)

Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.

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Prediction of human mRNA donor and acceptor sites from the DNA sequence.

S Brunak, J Engelbrecht, S. KNUDSEN (1991)

Artificial neural networks have been applied to the prediction of splice site location in human pre-mRNA. A joint prediction scheme where prediction of transition regions between introns and exons regulates a cutoff level for splice site assignment was able to predict splice site locations with confidence levels far better than previously reported in the literature. The problem of predicting donor and acceptor sites in human genes is hampered by the presence of numerous amounts of false positives: here, the distribution of these false splice sites is examined and linked to a possible scenario for the splicing mechanism in vivo. When the presented method detects 95% of the true donor and acceptor sites, it makes less than 0.1% false donor site assignments and less than 0.4% false acceptor site assignments. For the large data set used in this study, this means that on average there are one and a half false donor sites per true donor site and six false acceptor sites per true acceptor site. With the joint assignment method, more than a fifth of the true donor sites and around one fourth of the true acceptor sites could be detected without accompaniment of any false positive predictions. Highly confident splice sites could not be isolated with a widely used weight matrix method or by separate splice site networks. A complementary relation between the confidence levels of the coding/non-coding and the separate splice site networks was observed, with many weak splice sites having sharp transitions in the coding/non-coding signal and many stronger splice sites having more ill-defined transitions between coding and non-coding.

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Author and article information

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André P. Gerber: Role: Academic Editor

Journal

Journal ID (nlm-ta): Biomolecules

Journal ID (iso-abbrev): Biomolecules

Journal ID (publisher-id): biomolecules

Title: Biomolecules

Publisher: MDPI

ISSN (Electronic): 2218-273X

Publication date (Electronic): 13 May 2015

Publication date Collection: June 2015

Volume: 5

Issue: 2

Pages: 893-909

Affiliations

[1 ]Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 70 Ship Street, Providence, RI 02903, USA; E-Mails: alger_fredericks@ 123456brown.edu (A.M.F.); kamil_cygan@ 123456brown.edu (K.J.C.); b.anthony.brown830@ 123456gmail.com (B.A.B.)

[2 ]Center for Computational Molecular Biology, Brown University, 115 Waterman Street, Providence, RI 02912, USA

Author notes

[†]

These authors contributed equally to this work.

[* ]Author to whom correspondence should be addressed; E-Mail: fairbrother@ 123456brown.edu ; Tel./Fax: +1-401-863-6215.

Article

Publisher ID: biomolecules-05-00893

DOI: 10.3390/biom5020893

PMC ID: 4496701

PubMed ID: 25985083

SO-VID: b1a60bf4-70e7-475e-bd5b-c42c37f14907

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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

RNA-Binding Proteins: Splicing Factors and Disease

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Abstract

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RNA drug delivery

Most cited references 66

HITS-CLIP yields genome-wide insights into brain alternative RNA processing

RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.

Prediction of human mRNA donor and acceptor sites from the DNA sequence.

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