Gene regulation by alternative splicing and nonsense-mediated decay

Many alternative splicing events create premature stop codons in mRNAs that will trigger degradation of the mRNA by nonsense-mediated decay (NMD), suggesting that alternative splicing coupled with NMD may regulate gene expression post-transcriptionally, I tested this hypothesis in mouse by blocking NMD and measuring splicing isoform representation using splicing-sensitive microarrays. I identified a class of alternative splicing events that produce NMD sensitive isoforms through inclusion of highly conserved or ultraconserved stop codon exons in vertebrates.;Further analysis on human ultraconserved elements show that NMD of mRNAs for splicing activators such as SR proteins is triggered by splicing activation events, whereas NMD of the mRNAs for negatively acting hnRNP proteins is triggered by splicing repression, suggesting that the extreme genomic conservation surrounding these regulatory splicing events within splicing factor genes have evolutionary importance to maintaining the homeostasis of splicing factor levels in the vertebrate cell.;Gene regulation by alternative splicing and NMD is not restricted to RNA splicing factor genes. Using catabolic enzyme gene SSAT as an example, I showed that structured mRNA around SSAT stop codon exon is important to NMD-coupled alternative splicing regulation.