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, I3 4
Barash, Y3
Shai, O3
He, D3 4
Zielenski, J4
Tsui, LC2
Parkinson, J3 4
Frey, BJ3
Rommens, JM3 4
Blencowe, BJ1 3
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
2011 Impact Factor: 13.608
2011 SCImago Journal Rankings: 3.833
DOIhttp://dx.doi.org/10.1101/gr.073155.107
PubMed Central IDPMC2493427
ReferencesReferences in Scopus
DC Field
Value
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
2011 Impact Factor: 13.608
2011 SCImago Journal Rankings: 3.833
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
Author Affiliations
  1. University of Toronto, Terrence Donnelly Centre for Cellular and Biomolecular Research
  2. The University of Hong Kong
  3. University of Toronto
  4. Hospital for Sick Children, Toronto