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Article: A systematic analysis of intronic sequences downstream of 5′ splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation
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TitleA systematic analysis of intronic sequences downstream of 5′ splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation
 
AuthorsAznarez, I2 3
Barash, Y2
Shai, O2
He, D2 3
Zielenski, J3
Tsui, LC1
Parkinson, J3 2
Frey, BJ2
Rommens, JM2 3
Blencowe, BJ2
 
Issue Date2008
 
PublisherCold Spring Harbor Laboratory Press, Publications Department. The Journal's web site is located at http://www.genome.org
 
CitationGenome Research, 2008, v. 18 n. 8, p. 1247-1258 [How to Cite?]
DOI: http://dx.doi.org/10.1101/gr.073155.107
 
AbstractTo identify human intronic sequences associated with 5′ splice site recognition, we performed a systematic search for motifs enriched in introns downstream of both constitutive and alternative cassette exons. Significant enrichment was observed for U-rich motifs within 100 nucleotides downstream of 5′ splice sites of both classes of exons, with the highest enrichment between positions +6 and +30. Exons adjacent to U-rich intronic motifs contain lower frequencies of exonic splicing enhancers and higher frequencies of exonic splicing silencers, compared with exons not followed by U-rich intronic motifs. These findings motivated us to explore the possibility of a widespread role for U-rich motifs in promoting exon inclusion. Since cytotoxic granule-associated RNA binding protein (TIA1) and TIA1-like 1 (TIAL1; also known as TIAR) were previously shown in vitro to bind to U-rich motifs downstream of 5′ splice sites, and to facilitate 5′ splice site recognition in vitro and in vivo, we investigated whether these factors function more generally in the regulation of splicing of exons followed by U-rich intronic motifs. Simultaneous knockdown of TIA1 and TIAL1 resulted in increased skipping of 36/41 (88%) of alternatively spliced exons associated with U-rich motifs, but did not affect 32/33 (97%) alternatively spliced exons that are not associated with U-rich motifs. The increase in exon skipping correlated with the proximity of the first U-rich motif and the overall "U-richness" of the adjacent intronic region. The majority of the alternative splicing events regulated by TIA1/TIAL1 are conserved in mouse, and the corresponding genes are associated with diverse cellular functions. Based on our results, we estimate that ∼15% of alternative cassette exons are regulated by TIA1/TIAL1 via U-rich intronic elements. ©2008 by Cold Spring Harbor Laboratory Press.
 
ISSN1088-9051
2013 Impact Factor: 13.852
 
DOIhttp://dx.doi.org/10.1101/gr.073155.107
 
PubMed Central IDPMC2493427
 
ISI Accession Number IDWOS:000258116100006
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorAznarez, I
 
dc.contributor.authorBarash, Y
 
dc.contributor.authorShai, O
 
dc.contributor.authorHe, D
 
dc.contributor.authorZielenski, J
 
dc.contributor.authorTsui, LC
 
dc.contributor.authorParkinson, J
 
dc.contributor.authorFrey, BJ
 
dc.contributor.authorRommens, JM
 
dc.contributor.authorBlencowe, BJ
 
dc.date.accessioned2011-09-07T02:21:38Z
 
dc.date.available2011-09-07T02:21:38Z
 
dc.date.issued2008
 
dc.description.abstractTo identify human intronic sequences associated with 5′ splice site recognition, we performed a systematic search for motifs enriched in introns downstream of both constitutive and alternative cassette exons. Significant enrichment was observed for U-rich motifs within 100 nucleotides downstream of 5′ splice sites of both classes of exons, with the highest enrichment between positions +6 and +30. Exons adjacent to U-rich intronic motifs contain lower frequencies of exonic splicing enhancers and higher frequencies of exonic splicing silencers, compared with exons not followed by U-rich intronic motifs. These findings motivated us to explore the possibility of a widespread role for U-rich motifs in promoting exon inclusion. Since cytotoxic granule-associated RNA binding protein (TIA1) and TIA1-like 1 (TIAL1; also known as TIAR) were previously shown in vitro to bind to U-rich motifs downstream of 5′ splice sites, and to facilitate 5′ splice site recognition in vitro and in vivo, we investigated whether these factors function more generally in the regulation of splicing of exons followed by U-rich intronic motifs. Simultaneous knockdown of TIA1 and TIAL1 resulted in increased skipping of 36/41 (88%) of alternatively spliced exons associated with U-rich motifs, but did not affect 32/33 (97%) alternatively spliced exons that are not associated with U-rich motifs. The increase in exon skipping correlated with the proximity of the first U-rich motif and the overall "U-richness" of the adjacent intronic region. The majority of the alternative splicing events regulated by TIA1/TIAL1 are conserved in mouse, and the corresponding genes are associated with diverse cellular functions. Based on our results, we estimate that ∼15% of alternative cassette exons are regulated by TIA1/TIAL1 via U-rich intronic elements. ©2008 by Cold Spring Harbor Laboratory Press.
 
dc.description.naturelink_to_OA_fulltext
 
dc.identifier.citationGenome Research, 2008, v. 18 n. 8, p. 1247-1258 [How to Cite?]
DOI: http://dx.doi.org/10.1101/gr.073155.107
 
dc.identifier.citeulike6702616
 
dc.identifier.doihttp://dx.doi.org/10.1101/gr.073155.107
 
dc.identifier.epage1258
 
dc.identifier.isiWOS:000258116100006
 
dc.identifier.issn1088-9051
2013 Impact Factor: 13.852
 
dc.identifier.issue8
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2493427
 
dc.identifier.pmid18456862
 
dc.identifier.scopuseid_2-s2.0-48949103996
 
dc.identifier.spage1247
 
dc.identifier.urihttp://hdl.handle.net/10722/138687
 
dc.identifier.volume18
 
dc.languageeng
 
dc.publisherCold Spring Harbor Laboratory Press, Publications Department. The Journal's web site is located at http://www.genome.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofGenome Research
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAlternative Splicing
 
dc.subject.meshIntrons
 
dc.subject.meshPoly(A)-Binding Proteins - antagonists and inhibitors - genetics - physiology
 
dc.subject.meshRNA-Binding Proteins - antagonists and inhibitors - genetics - physiology
 
dc.subject.meshRegulatory Sequences, Ribonucleic Acid
 
dc.titleA systematic analysis of intronic sequences downstream of 5′ splice sites reveals a widespread role for U-rich motifs and TIA1/TIAL1 proteins in alternative splicing regulation
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. University of Toronto
  3. Hospital for Sick Children University of Toronto