SnapShot: The Splicing Regulatory Machinery

Gabut, Mathieu; Chaudhry, Sidharth; Blencowe, Benjamin J.

doi:10.1016/j.cell.2008.03.010

Cited by 60 publications

(64 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In fact, large fraction of AS undergoes cell-specific regulation in which splicing pathways are modulated according to cell type, developmental stage, gender, or in response to external stimuli (Faustino and Cooper, 2003). Despite the growing list of mammalian protein factors known to regulate AS (Gabut et al, 2008), we still lack the information that allows us to predict cell-and tissue-specific AS or even which protein factors are most likely to target which exons (Blencowe, 2006). …”

Section: Alternative Splicing and Biological Complexity: One Gene Mamentioning

confidence: 99%

“…Alternative splicing is also known to play numerous critical roles in both normal and disease processes (Blencowe, 2006;Gabut et al, 2008). By definition, AS is the process by which pairs of ss are differentially selected to generate multiple mRNA variants from a single precursor (pre-) mRNA (Gabut et al, 2008). The greater frequency of AS events in mammals than in vertebrates again reflects the contribution of AS to this biological complexity (Kim et al, 2004).…”

Section: Alternative Splicing and Biological Complexity: One Gene Mamentioning

confidence: 99%

“…Alternative pre-mRNA splicing is believed to be a major mechanism to bridge the gap between the gene and protein number (Graveley, 2001;Maniatis and Tasic, 2002), thereby allowing the expansion of the proteome and regulation of gene expression in higher eukaryotes. Alternative splicing is also known to play numerous critical roles in both normal and disease processes (Blencowe, 2006;Gabut et al, 2008). By definition, AS is the process by which pairs of ss are differentially selected to generate multiple mRNA variants from a single precursor (pre-) mRNA (Gabut et al, 2008).…”

Section: Alternative Splicing and Biological Complexity: One Gene Mamentioning

confidence: 99%

See 2 more Smart Citations

Systematic evaluation of the effect of common SNPs on pre-mRNA splicing

et al. 2009

View full text Add to dashboard Cite

Section: Alternative Splicing and Biological Complexity: One Gene Mamentioning

confidence: 99%

Section: Alternative Splicing and Biological Complexity: One Gene Mamentioning

confidence: 99%

Section: Alternative Splicing and Biological Complexity: One Gene Mamentioning

confidence: 99%

See 1 more Smart Citation

Systematic evaluation of the effect of common SNPs on pre-mRNA splicing

et al. 2009

View full text Add to dashboard Cite

“…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)(7)(8).…”

mentioning

confidence: 99%

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.

458

652

View full text Add to dashboard Cite

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 ...

show abstract

“…The coordinated binding of combinations of regulatory proteins to their binding sites modulate the expression of specific transcript isoforms in a cell/tissue type-, development stage-, disease-and/or other condition-specific manners and may also promote or repress the formation of the spliceosome, the large (~60S) RNA-protein machinery that catalyzes intron removal. A growing list of mammalian protein factors involved in splicing regulation and their target sites in the pre-mRNA has been reported in the literature [2]. In order to establish a curated and retrievable repository of splicing regulatory factors and target sites for human genes we have recently created SpliceAid [4] that can also be used to find putative regulatory motifs in user submitted sequences.…”

Section: Motivationsmentioning

confidence: 99%

SpliceAid-F: a database of human splicing factors and their RNA binding sites

Giulietti

Piva

D’Antonio³

et al. 2012

EMBnet j.

View full text Add to dashboard Cite

MotivationsThe pre-mRNA sequences of eukaryotes harbour multiple information layers in addition to the one specifying the aminoacid sequence. Indeed, specific signals regulating the splicing process, RNA folding, capping, polyadenylation, stability and nuclear export, overlap each other and with the coding information. Mutagenesis experiments have highlighted that splicing regulatory elements are scattered in the entire pre-mRNA sequence and that all nucleotide positions are potentially involved in the generation of the specific splicing pattern through the specific interaction with trans-acting RNA-binding proteins. In particular, the identification of cis-regulatory motifs in exonic regions, such as exonic splicing enhancers (ESEs) or silencers (ESSs), superimposed on the coding sequence of the gene can be driven by the observation of purifying selection occurring at synonymous codons [5]. The coordinated binding of combinations of regulatory proteins to their binding sites modulate the expression of specific transcript isoforms in a cell/tissue type-, development stage-, disease-and/or other condition-specific manners and may also promote or repress the formation of the spliceosome, the large (~60S) RNA-protein machinery that catalyzes intron removal. A growing list of mammalian protein factors involved in splicing regulation and their target sites in the pre-mRNA has been reported in the literature [2]. In order to establish a curated and retrievable repository of splicing regulatory factors and target sites for human genes we have recently created SpliceAid [4] that can also be used to find putative regulatory motifs in user submitted sequences. As a further evolution of SpliceAid, we present here SpliceAid-F, a database compilation of splicing regulatory factors and their experimentally validated target RNAs extracted from an exhaustive hand-curated literature search.

show abstract

SnapShot: The Splicing Regulatory Machinery

Cited by 60 publications

References 15 publications

Systematic evaluation of the effect of common SNPs on pre-mRNA splicing

Systematic evaluation of the effect of common SNPs on pre-mRNA splicing

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

SpliceAid-F: a database of human splicing factors and their RNA binding sites

Contact Info

Product

Resources

About