Abstract
Discovery and Analysis of Evolutionarily Conserved Intronic Splicing Regulatory Elements in Mammalian Genomes
Highlights
Considering that the human genome contains upwards of 20,000 genes with an average of eight to ten exons per gene, it is remarkable that the RNA splicing machinery faithfully distinguishes exons from intronic sequences that are 100- to 1,000-fold larger in size
It reveals a set of evolutionarily conserved intronic splicing regulatory element (ISRE), and hundreds of candidate ISRE-regulated exons conserved across mammalian genomes
84% and 94% of tested ISREs were shown to suppress intron-proximal 59ss and 39ss in competing splice site reporter constructs in human cells, demonstrating that most ISREs can affect splicing
Summary
Considering that the human genome contains upwards of 20,000 genes with an average of eight to ten exons per gene, it is remarkable that the RNA splicing machinery faithfully distinguishes exons from intronic sequences that are 100- to 1,000-fold larger in size. Many studies show that the fidelity of splicing relies on cooperative interaction between the splicesomal complex and splicing trans factors (reviewed in [1]). Simple models of exon recognition depict trans factors binding to splicing regulatory elements (SREs) in cis that are in intronic regions proximal to the exon, or within the exon itself, resulting in either increased exon usage (splicing enhancers), or decreased splice site recognition (splicing silencers) [2,3,4]. In addition to regulating constitutive splicing (e.g., where a gene has only one isoform), SREs are important in regulating tissue-specific and developmentally regulated alternative splicing events [2,3,4]. Evidence that as many as 75% of human genes undergo alternative splicing, whereby multiple isoforms are derived from the same genic location, underscores the complexity of RNA splicing regulation [5]. A complete catalog of SREs is necessary to improve our understanding of the mechanisms controlling splicing, for it will enable rapid diagnosis and treatment of splicing-associated diseases [7]
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