Abstract
BackgroundAlternative splicing is one of the key mechanisms that generate biological diversity. Even though alternative splicing also occurs in the 5' and 3' untranslated regions (UTRs) of mRNAs, the understanding of the significance and the regulation of these variations is rather limited.ResultsWe investigated 5' UTR mRNA variants of the mouse Gli1 oncogene, which is the terminal transcriptional effector of the Hedgehog (HH) signaling pathway. In addition to identifying novel transcription start sites, we demonstrated that the expression ratio of the Gli1 splice variants in the 5' UTR is regulated by the genotype of the mouse strain analyzed. The GT allele, which contains the consensus intronic dinucleotides at the 5' splice site of intron 1B, favors exon 1B inclusion, while the GC allele, having a weaker 5' splice site sequence, promotes exon 1B skipping. Moreover, the alternative Gli1 5' UTRs had an impact on translational capacity, with the shorter and the exon 1B-skipped mRNA variants being most effective.ConclusionsOur findings implicate novel, genome-based mechanisms as regulators of the terminal events in the mouse HH signaling cascade.
Highlights
Alternative splicing is one of the key mechanisms that generate biological diversity
Identification of novel transcription start sites in the mouse Glioma associated oncogene 1 (Gli1) gene In a previous report, we have shown the presence of novel human GLI1 splice variants, which skip exons 2 and 3 [19]
Wang and Rothnagel had earlier reported the skipping of exon 1A and/or exon 1B in mouse Gli1 [18]
Summary
Alternative splicing is one of the key mechanisms that generate biological diversity. A genome-wide screening of alternative splicing and transcriptional initiation estimated that a significant number of genes are differentially spliced within 5' and 3' untranslated regions (UTRs) [4]. Another genome-wide analysis identified 324 out of 17897 genes that display associations between flanking single nucleotide polymorphisms (SNPs) and gene expression/alternative transcription, demonstrating the regulatory effects of genetic variation in human populations [5]. These non-bias/genome-wide analyses highlight the importance of alternative splicing/promoter. Analysis of variable 5' UTRs in the TGFbeta, BRCA1 and MDM2 genes, have indicated that the shorter UTR variants are translated more efficiently [7]
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