title: Ultraconserved elements are associated with homeostatic control of splicing regulators by alternative splicing and nonsense-mediated decay.
abstract: Many alternative splicing events create RNAs with premature stop codons, suggesting that alternative splicing coupled with nonsense-mediated decay (AS-NMD) may regulate gene expression post-transcriptionally. We tested this idea in mice by blocking NMD and measuring changes in isoform representation using splicing-sensitive microarrays. We found a striking class of highly conserved stop codon-containing exons whose inclusion renders the transcript sensitive to NMD. A genomic search for additional examples identified>50 such exons in genes with a variety of functions. These exons are unusually frequent in genes that encode splicing activators and are unexpectedly enriched in the so-called "ultraconserved" elements in the mammalian lineage. Further analysis 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, a polarity consistent with widespread homeostatic control of splicing regulator gene expression. We suggest that the extreme genomic conservation surrounding these regulatory splicing events within splicing factor genes demonstrates the evolutionary importance of maintaining tightly tuned homeostasis of RNA-binding protein levels in the vertebrate cell.
authors: Center for Molecular Biology of RNA and Department of Molecular, Cell, and Developmental Biology, University of California at Santa Cruz, Santa Cruz, California 95064, USA.
authors: Julie Z
authors: JZ
authors: Ni
authors: Leslie
authors: L
authors: Grate
authors: John Paul
authors: JP
authors: Donohue
authors: Christine
authors: C
authors: Preston
authors: Naomi
authors: N
authors: Nobida
authors: Georgeann
authors: G
authors: O'Brien
authors: Lily
authors: L
authors: Shiue
authors: Tyson A
authors: TA
authors: Clark
authors: John E
authors: JE
authors: Blume
authors: Manuel
authors: M
authors: Ares
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018389:Codon, Nonsense; D018388:Codon, Terminator; D017124:Conserved Sequence; D005091:Exons; D005786:Gene Expression Regulation; D006706:Homeostasis; D051379:Mice; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator; D012333:RNA, Messenger