Dataset Information

Peroxisome Proliferator-activated Receptor ? Coactivator-1 ? Isoforms Selectively Regulate Multiple Splicing Events on Target Genes.

ABSTRACT: Endurance and resistance exercise training induces specific and profound changes in the skeletal muscle transcriptome. Peroxisome proliferator-activated receptor ? coactivator-1 ? (PGC-1?) coactivators are not only among the genes differentially induced by distinct training methods, but they also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. Although endurance training preferentially induces PGC-1?1 expression, resistance exercise activates the expression of PGC-1?2, -?3, and -?4. These three alternative PGC-1? isoforms lack the arginine/serine-rich (RS) and RNA recognition motifs characteristic of PGC-1?1. Discrete functions for PGC-1?1 and -?4 have been described, but the biological role of PGC-1?2 and -?3 remains elusive. Here we show that different PGC-1? variants can affect target gene splicing through diverse mechanisms, including alternative promoter usage. By analyzing the exon structure of the target transcripts for each PGC-1? isoform, we were able to identify a large number of previously unknown PGC-1?2 and -?3 target genes and pathways in skeletal muscle. In particular, PGC-1?2 seems to mediate a decrease in the levels of cholesterol synthesis genes. Our results suggest that the conservation of the N-terminal activation and repression domains (and not the RS/RNA recognition motif) is what determines the gene programs and splicing options modulated by each PGC-1? isoform. By using skeletal muscle-specific transgenic mice for PGC-1?1 and -?4, we could validate, in vivo, splicing events observed in in vitro studies. These results show that alternative PGC-1? variants can affect target gene expression both quantitatively and qualitatively and identify novel biological pathways under the control of this system of coactivators.

SUBMITTER: Martinez-Redondo V

PROVIDER: S-EPMC4946932 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Peroxisome Proliferator-activated Receptor γ Coactivator-1 α Isoforms Selectively Regulate Multiple Splicing Events on Target Genes.

Martínez-Redondo Vicente V Jannig Paulo R PR Correia Jorge C JC Ferreira Duarte M S DM Cervenka Igor I Lindvall Jessica M JM Sinha Indranil I Izadi Manizheh M Pettersson-Klein Amanda T AT Agudelo Leandro Z LZ Gimenez-Cassina Alfredo A Brum Patricia C PC Dahlman-Wright Karin K Ruas Jorge L JL

The Journal of biological chemistry 20160526 29

Endurance and resistance exercise training induces specific and profound changes in the skeletal muscle transcriptome. Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) coactivators are not only among the genes differentially induced by distinct training methods, but they also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. Although endurance training preferentially induces PGC-1α1 expression, resistance exercise act ...[more]

PMID: 27231350

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Project description:Peroxisome proliferator-activated receptor γ (PPARγ) has 2 protein isoforms (PPARγ1 and PPARγ2) generated by alternative promoter usage and alternative splicing. However, their functional uniqueness and similarity remain unclear. In the study, we investigated the effects of lentivirus-mediated overexpression of PPARγ1 and PPARγ2 on proliferation, apoptosis, and differentiation of the immortalized chicken preadipocytes. Cell Counting Kit-8 assay showed PPARγ1 and PPARγ2 overexpression markedly suppressed cell proliferation, and fluorescence activated cell sorting analysis showed that PPARγ1 and PPARγ2 overexpression caused cell cycle arrest at G0/G1 phase. Cell death detection ELISA analysis showed both PPARγ1 and PPARγ2 overexpression induced cell apoptosis. Oil red O staining and gene expression analysis showed both PPARγ1 and PPARγ2 overexpression promoted preadipocyte differentiation. In the presence of PPARγ ligand, rosiglitazone, PPARγ2 overexpression was more potent in inducing apoptosis, promoting adipogenesis, and suppressing cell proliferation than PPARγ1 overexpression. We further explored the molecular basis for their functional differences. Reporter gene assay showed that under ligand conditions, PPARγ2 overexpression resulted in 1.68-fold increase in transcription activity compared with PPARγ1. Electrophoretic mobility shift assay showed both PPARγ1 and PPARγ2 could bind to PPAR response element (PPRE) as heterodimer with retinoid X receptor alpha, and by comparison, PPARγ2 had a higher affinity for PPRE than PPARγ1. Reporter gene assay showed expression PPARγ1 and PPARγ2 similarly induced fatty acid synthase and adipocyte fatty acid-binding protein promoter activity but differentially induced lipoprotein lipase and perilipin 1 promoter activities. Coimmunoprecipitation analysis showed that PPARγ1 and PPARγ2 interacted similarly with the coactivators, Tat-interacting protein 60. Taken together, our results demonstrate that PPARγ1 and PPARγ2 differentially regulate preadipocyte proliferation, apoptosis, and differentiation as a result of their distinct and overlapping molecular functions.

Dataset Information

Peroxisome Proliferator-activated Receptor ? Coactivator-1 ? Isoforms Selectively Regulate Multiple Splicing Events on Target Genes.

Publications

Peroxisome Proliferator-activated Receptor γ Coactivator-1 α Isoforms Selectively Regulate Multiple Splicing Events on Target Genes.

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