A Polar Mechanism Coordinates Different Regions of Alternative Splicing within a Single Gene

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 o...

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Bibliographic Details
Published in:Molecular cell 2005-08, Vol.19 (3), p.393-404
Main Authors: Fededa, Juan P., Petrillo, Ezequiel, Gelfand, Mikhail S., Neverov, Alexei D., Kadener, Sebastián, Nogués, Guadalupe, Pelisch, Federico, Baralle, Francisco E., Muro, Andrés F., Kornblihtt, Alberto R.
Format: Article
Language:English
Subjects:
Alleles
Alpha-Globulins - genetics
Alternative Splicing
Animals
Antigens, Viral, Tumor - genetics
Cell Line, Tumor
Cercopithecus aethiops
Computational Biology
COS Cells
Dichlororibofuranosylbenzimidazole - pharmacology
DNA-Binding Proteins - genetics
Exons - genetics
Fibroblasts - drug effects
Fibroblasts - metabolism
Fibronectins - genetics
Genes - genetics
Humans
Mice
Mice, Knockout
Models, Genetic
Nuclear Proteins - genetics
Promoter Regions, Genetic - genetics
Protein Isoforms - genetics
RNA Polymerase II - antagonists & inhibitors
RNA Polymerase II - metabolism
RNA Splicing
RNA-Binding Proteins - genetics
Serine-Arginine Splicing Factors
Transcription Factors - genetics
Transfection
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Description
Summary: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.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2005.06.035