A polar mechanism coordinates different regions of alternative splicing within a single gene

Juan P. Fededa, Ezequiel Petrillo, Mikhail S. Gelfand, Alexei D. Neverov, Sebastián Kadener, Guadalupe Nogués, Federico Pelisch, Francisco E. Baralle, Andrés F. Muro, Alberto R. Kornblihtt

Research output: Contribution to journalArticlepeer-review

48 Citations (Scopus)

Abstract

Alternative splicing plays a key role in generating protein diversity. Transfections with minigenes revealed coordination between two distant, alternatively spliced exons in the same gene. Mutations that either inhibit or stimulate inclusion of the upstream alternative exon deeply affect inclusion of the downstream one. However, similar mutations at the downstream alternative exon have little effect on the upstream one. This polar effect is promoter specific and is enhanced by inhibition of transcriptional elongation. Consistently, cells from mutant mice with either constitutive or null inclusion of a fibronectin alternative exon revealed coordination with a second alternative splicing region, located far downstream. Using allele-specific RT-PCR, we demonstrate that this coordination occurs in cis and is also affected by transcriptional elongation rates. Bioinformatics supports the generality of these findings, indicating that 25% of human genes contain multiple alternative splicing regions and identifying several genes with nonrandom distribution of mRNA isoforms at two alternative regions.

Original languageEnglish
Pages (from-to)393-404
Number of pages12
JournalMolecular Cell
Volume19
Issue number3
DOIs
Publication statusPublished - 5 Aug 2005
Externally publishedYes

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