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The polypyrimidine tract binding protein regulates desaturase alternative splicing and PUFA composition.

ABSTRACT: The ?6 desaturase, encoded by FADS2, plays a crucial role in omega-3 and omega-6 fatty acid synthesis. These fatty acids are essential components of the central nervous system, and they act as precursors for eicosanoid signaling molecules and as direct modulators of gene expression. The polypyrimidine tract binding protein (PTB or hnRNP I) is a splicing factor that regulates alternative pre-mRNA splicing. Here, PTB is shown to bind an exonic splicing silencer element and repress alternative splicing of FADS2 into FADS2 AT1. PTB and FADS2AT1 were inversely correlated in neonatal baboon tissues, implicating PTB as a major regulator of tissue-specific FADS2 splicing. In HepG2 cells, PTB knockdown modulated alternative splicing of FADS2, as well as FADS3, a putative desaturase of unknown function. Omega-3 fatty acids decreased by nearly one half relative to omega-6 fatty acids in PTB knockdown cells compared with controls, with a particularly strong decrease in eicosapentaenoic acid (EPA) concentration and its ratio to arachidonic acid (ARA). This is a rare demonstration of a mechanism specifically altering the cellular omega-3 to omega-6 fatty acid ratio without any change in diet/media. These findings reveal a novel role for PTB, regulating availability of membrane components and eicosanoid precursors for cell signaling.

SUBMITTER: Reardon HT

PROVIDER: S-EPMC3220295 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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The polypyrimidine tract binding protein regulates desaturase alternative splicing and PUFA composition.

Reardon Holly T HT Park Woo Jung WJ Zhang Jimmy J Lawrence Peter P Kothapalli Kumar S D KSD Brenna J Thomas JT

Journal of lipid research 20111006 12

The Δ6 desaturase, encoded by FADS2, plays a crucial role in omega-3 and omega-6 fatty acid synthesis. These fatty acids are essential components of the central nervous system, and they act as precursors for eicosanoid signaling molecules and as direct modulators of gene expression. The polypyrimidine tract binding protein (PTB or hnRNP I) is a splicing factor that regulates alternative pre-mRNA splicing. Here, PTB is shown to bind an exonic splicing silencer element and repress alternative spli ...[more]

PMID: 21980057

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Project description:Alternative splicing (AS) generates transcript variants by the definition of different exonic and intronic regions and causes a massive expansion of transcriptome diversity. Changes in AS patterns have been found to be linked to manifold biological processes, yet fundamental aspects such as the regulation of AS and the functional implications of altered AS programs largely remain to be addressed. In this work, widespread AS regulation by Arabidopsis Polypyrimidine tract-binding protein homologues (AtPTBs) was revealed. In total 452 AS events derived from 308 distinct genes were found to be responsive to the levels of the splicing factors AtPTB1 and AtPTB2, which predominantly triggered splicing of regulated introns, inclusion of cassette exons, and usage of upstream 5' splice sites. In contrast, alternative 3' splice site events were strongly underrepresented among the AtPTB1/2 targets and no major AS regulatory function of the distantly related AtPTB3 was found. Dependent on their position within the mRNA, AtPTB-regulated events can both modify the untranslated regions and give rise to alternative protein products. Gene ontology analysis revealed a connection of AtPTB-mediated AS control with diverse biological processes, and the functional implications of selected AS events were further elucidated in the context of seed germination and flowering time control. Specifically, AtPTB misexpression changes AS of the PHYTOCHROME INTERACTING FACTOR 6 (PIF6) pre-mRNA, coinciding with altered rates of abscisic acid-dependent seed germination. Furthermore, AS patterns as well as the expression of key flowering regulators were massively changed in an AtPTB1/2 level-dependent manner. In conclusion, our work has revealed widespread AS regulatory functions of the AtPTB splicing factors with important functional implications in various fundamental processes of Arabidopsis development. Analysis of alternative splicing patterns in plants with increased and decreased levels of the 3 Arabidopsis Polypyrimidine-tract binding protein homologues in comparison to wild type samples, determined in duplicates

Dataset Information

The polypyrimidine tract binding protein regulates desaturase alternative splicing and PUFA composition.

Publications

The polypyrimidine tract binding protein regulates desaturase alternative splicing and PUFA composition.

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