General and Specific Functions of Exonic Splicing Silencers in Splicing Control

Wang, Zefeng; Xiao, Xinshu; Nostrand, Eric L. Van; Burge, Christopher B.

doi:10.1016/j.molcel.2006.05.018

Cited by 170 publications

(218 citation statements)

References 32 publications

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“…Interestingly, CELF motifs were associated with increased exon inclusion when located in the first 250 bases of the downstream intron and decreased exon inclusion when located in the last 250 bases of the downstream intron. This pattern suggests that, like some other families of factors, the CELF family splicing factors may function to activate or repress splicing in a location-dependent manner (20,21). The MBNL motif UGCGC was highly conserved in the last 250 bases of the upstream introns and was among the most significant motifs in the regression analysis being associated with decreased exon inclusion compared with both E14 and adult data at all 5 time points.…”

Section: Binding Motifs For Known Splicing Factors Including Celf Andmentioning

confidence: 78%

A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart

Kalsotra

Xiao

Ward

et al. 2008

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

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652

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From a large-scale screen using splicing microarrays and RT-PCR, we identified 63 alternative splicing (AS) events that are coordinated in 3 distinct temporal patterns during mouse heart development. More than half of these splicing transitions are evolutionarily conserved between mouse and chicken. Computational analysis of the introns flanking these splicing events identified enriched and conserved motifs including binding sites for CUGBP and ETR-3-like factors (CELF), muscleblind-like (MBNL) and Fox proteins. We show that CELF proteins are down-regulated >10-fold during heart development, and MBNL1 protein is concomitantly up-regulated nearly 4-fold. Using transgenic and knockout mice, we show that reproducing the embryonic expression patterns for CUGBP1 and MBNL1 in adult heart induces the embryonic splicing patterns for more than half of the developmentally regulated AS transitions. These findings indicate that CELF and MBNL proteins are determinative for a large subset of splicing transitions that occur during postnatal heart development.CUGBP and ETR-3-like factors ͉ heart development ͉ muscleblind-like ͉ splicing microarray C oordinated control of alternative splicing (AS) on a genomewide scale has the potential to drive proteome transitions with wide-ranging and critical biological consequences (1, 2). Disruption of splicing and its regulation, therefore, is implicated in disease causation and susceptibility (3). Splicing is regulated by RNAbinding proteins that bind to cis-regulatory elements near the splice sites. Some of the best-characterized splicing regulators include the serine-arginine (SR)-rich family, hnRNP proteins, and the Nova, PTB, FOX, TIA, CUGBP and ETR-3-like factors (CELF), and muscleblind-like (MBNL) families (4, 5). CELF and MBNL proteins were first characterized as factors involved in the pathogenesis of myotonic dystrophy and were subsequently shown to be direct regulators of AS (6-8). Recent advances in microarray and computational technologies have allowed comprehensive analyses of individual exons on a genome-wide scale, providing the ability to identify commonly regulated splicing events (9-12).With some exceptions (13,14), most large-scale analyses of regulated splicing have focused primarily on differences between adult tissues and tissues/cell cultures depleted for a splicing regulator rather than normal physiological transitions within a single tissue (9)(10)(11)15). Developmental transitions provide an excellent opportunity to identify and determine the roles for coordinated splicing regulation associated with normal physiological change. The vertebrate heart is particularly attractive for such analysis because it undergoes extensive remodeling to meet the demands of increased workload in the developing organism (16). In addition, the heart has relatively low cellular complexity and little cell turnover (17) so that developmental splicing transitions reflect changes occurring within individual cells to a greater extent than in many other tissues. The physiological changes ...

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Section: Binding Motifs For Known Splicing Factors Including Celf Andmentioning

confidence: 78%

A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart

Kalsotra

Xiao

Ward

et al. 2008

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

Self Cite

448

652

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“…The collaboration between these elements results in the promotion or inhibition of splicesome assembly of the weak splice sites, respectively ( Fig. 2) (22,23). In general, the cis-acting elements function additively.…”

Section: Molecular Mechanisms Of Alternative Spicingmentioning

confidence: 99%

Mechanism of alternative splicing and its regulation

et al. 2014

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Abstract. Alternative splicing of precursor mRNA is an essential mechanism to increase the complexity of gene expression, and it plays an important role in cellular differentiation and organism development. Regulation of alternative splicing is a complicated process in which numerous interacting components are at work, including cis-acting elements and trans-acting factors, and is further guided by the functional coupling between transcription and splicing. Additional molecular features, such as chromatin structure, RNA structure and alternative transcription initiation or alternative transcription termination, collaborate with these basic components to generate the protein diversity due to alternative splicing.

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“…S4. (Stadler et al 2006;Wang et al 2006). Here we have presented evidence that mutations resulting in the creation of ESSs are also selected against, which would constitute a purifying selection.…”

Section: Eses and Esss Are Subject To Purifying Selectionmentioning

confidence: 99%

Positive selection acting on splicing motifs reflects compensatory evolution

Ke¹,

Zhang²,

Chasin³

2008

Genome Res.

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We have used comparative genomics to characterize the evolutionary behavior of predicted splicing regulatory motifs. Using base substitution rates in intronic regions as a calibrator for neutral change, we found a strong avoidance of synonymous substitutions that disrupt predicted exonic splicing enhancers or create predicted exonic splicing silencers. These results attest to the functionality of the hexameric motif set used and suggest that they are subject to purifying selection. We also found that synonymous substitutions in constitutive exons tend to create exonic splicing enhancers and to disrupt exonic splicing silencers, implying positive selection for these splicing promoting events. We present evidence that this positive selection is the result of splicing-positive events compensating for splicing-negative events as well as for mutations that weaken splice-site sequences. Such compensatory events include nonsynonymous mutations, synonymous mutations, and mutations at splice sites. Compensation was also seen from the fact that orthologous exons tend to maintain the same number of predicted splicing motifs. Our data fit a splicing compensation model of exon evolution, in which selection for splicing-positive mutations takes place to counter the effect of an ongoing splicing-negative mutational process, with the exon as a whole being conserved as a unit of splicing. In the course of this analysis, we observed that synonymous positions in general are conserved relative to intronic sequences, suggesting that messenger RNA molecules are rich in sequence information for functions beyond protein coding and splicing.[Supplemental material is available online at www.genome.org.]In addition to sequences that specify their cognate polypeptides, the open reading frames of eukaryotic messenger RNAs (mRNAs) are likely to contain additional information governing the functioning of these molecules; these functions include exon splicing and mRNA transport, localization, stability, and translation. If so, the evolution of mRNA sequence would be constrained by purifying selection against the loss of this information. This selection should be evident by examining the rate and quality of base substitutions that do not alter protein coding (synonymous substitutions) but may alter one of the abovementioned functions.Mutation rates in open reading frames have been extensively characterized by two parameters: K a , the rate of mutations that result in amino acid substitutions; and K s , the rate at synonymous sites. The latter has most often been assumed to reflect neutral change and has been used to normalize the mutation rates in a given gene, with the K a /K s ratio serving as an inverse measure of protein sequence conservation (Hurst 2002). More recently, the neutrality of K s has been challenged, with accumulating evidence for selection acting at synonymous sites (for reviews, see Chamary et al. 2006;Xing and Lee 2006). Some of this evidence has been based on comparisons between mutation rates in predicted exonic splicing e...

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General and Specific Functions of Exonic Splicing Silencers in Splicing Control

Cited by 170 publications

References 32 publications

A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart

A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart

Mechanism of alternative splicing and its regulation

Positive selection acting on splicing motifs reflects compensatory evolution

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