Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing
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- dc.contributor.author Tejedor Vaquero, Juan Ramón, 1984-ca
- dc.contributor.author Tilgner, Hagen, 1980-ca
- dc.contributor.author Iannone, Camilla, 1984-ca
- dc.contributor.author Guigó Serra, Rodericca
- dc.contributor.author Valcárcel, J. (Juan)ca
- dc.date.accessioned 2015-11-20T18:28:01Z
- dc.date.available 2016-04-23T02:00:04Z
- dc.date.issued 2015
- dc.description.abstract The OLR1 gene encodes the oxidized low-density lipoprotein receptor (LOX-1), which is responsible for the cellular uptake of oxidized LDL (Ox-LDL), foam cell formation in atheroma plaques and atherosclerotic plaque rupture. Alternative splicing (AS) of OLR1 exon 5 generates two protein isoforms with antagonistic functions in Ox-LDL uptake. Previous work identified six single nucleotide polymorphisms (SNPs) in linkage disequilibrium that influence the inclusion levels of OLR1 exon 5 and correlate with the risk of cardiovascular disease. Here we use minigenes to recapitulate the effects of two allelic series (Low- and High-Risk) on OLR1 AS and identify one SNP in intron 4 (rs3736234) as the main contributor to the differences in exon 5 inclusion, while the other SNPs in the allelic series attenuate the drastic effects of this key SNP. Bioinformatic, proteomic, mutational and functional high-throughput analyses allowed us to define regulatory sequence motifs and identify SR protein family members (SRSF1, SRSF2) and HMGA1 as factors involved in the regulation of OLR1 AS. Our results suggest that antagonism between SRSF1 and SRSF2/HMGA1, and differential recognition of their regulatory motifs depending on the identity of the rs3736234 polymorphism, influence OLR1 exon 5 inclusion and the efficiency of Ox-LDL uptake, with potential implications for atherosclerosis and coronary disease.ca
- dc.format.mimetype application/pdfca
- dc.identifier.citation Tejedor JR, Tilgner H, Iannone C, Guigó R, Valcárcel J. Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing. RNA. 2015;21(6):1187-202. DOI: 10.1261/rna.049890.115ca
- dc.identifier.doi http://dx.doi.org/10.1261/rna.049890.115
- dc.identifier.issn 1355-8382
- dc.identifier.uri http://hdl.handle.net/10230/25173
- dc.language.iso engca
- dc.publisher Cambridge University Pressca
- dc.relation.ispartof RNA. 2015;21(6):1187-202
- dc.rights © 2015 Tejedor et al. This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/bync/4.0/.ca
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0ca
- dc.subject.keyword OLR1
- dc.subject.keyword Alternative splicing
- dc.subject.keyword SNP
- dc.subject.keyword SR proteins
- dc.subject.keyword RRM
- dc.subject.keyword Linkage disequilibrium
- dc.subject.keyword Coronary disease
- dc.subject.other Alternative splicingca
- dc.subject.other Malalties coronàries
- dc.subject.other Empalmament (Genètica)
- dc.title Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicingca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca