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

FEDEDA, J. P.; PETRILLO, E.; GELFAND, M. S.; NEVEROV, A. D.; KADENER, S.; NOGUÉS, G.; PELISCH, F.; BARALLE, F. E.; MURO, A; KORNBLIHTT, A

MOLECULAR CELL

Año: 2005 vol. 19 p. 393 - 404

1097-2765

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, as expected for a co-transcriptional event. Bioinformatic analysis confirmed the importance of coordination by indicating that 25% of human genes contain multiple alternative splicing regions and showing several genes with two alternative regions with non-random distribution of mRNA exon combinations.