Unproductive splicing of SR genes associated with highly conserved and ultraconserved DNA elements

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Abstract
A function is defined for ultraconserved elements (UCEs), extragenic regions of eukaryotic genomes can show high degrees of conservation across species. It is also found that when alternative splicing (mediated by splicing regulator proteins) leads to UCE incorporation into the splicing regulator protein's mRNA, the mRNA is targeted for degradation. Thus, the UCEs help promote negative feedback regulation of the splicing regulator gene expression. The human and mouse genomes share a number of long, perfectly conserved nucleotide sequences, termed ultraconserved elements1. Whereas these regions can act as transcriptional enhancers when upstream of genes, those within genes are less well understood. In particular, the function of ultraconserved elements that overlap alternatively spliced exons of genes encoding RNA-binding proteins is unknown1,2. Here we report that in every member of the human SR family of splicing regulators, highly or ultraconserved elements are alternatively spliced, either as alternative ‘poison cassette exons’ containing early in-frame stop codons, or as alternative introns in the 3′ untranslated region. These alternative splicing events target the resulting messenger RNAs for degradation by means of an RNA surveillance pathway called nonsense-mediated mRNA decay. Mouse orthologues of the human SR proteins exhibit the same unproductive splicing patterns. Three SR proteins have been previously shown to direct splicing of their own transcripts, and one of these is known to autoregulate its expression by coupling alternative splicing with decay3,4,5; our results suggest that unproductive splicing is important for regulation of the entire SR family. We find that unproductive splicing associated with conserved regions has arisen independently in different SR genes, suggesting that splicing factors may readily acquire this form of regulation.