Peroxisome proliferator-activated receptor gamma coactivator-1alpha isoforms selectively regulate multiple splicing events on target genes.

ABSTRACT: Endurance and resistance exercise training induce specific and profound changes in the skeletal muscle transcriptome. PGC-1a; coactivators are not only among the genes differentially induced by distinct training methods, but also participate in the ensuing signaling cascades that allow skeletal muscle to adapt to each type of exercise. While endurance training preferentially induces PGC-1a1 expression, resistance exercise activates the expression of PGC-1a2, a3, and a4. These three alternative PGC-1a isoforms lack the arginine-serine (RS) and RNA Recognition Motifs (RRM) characteristic of PGC-1a1. Discrete functions for PGC-1a1 and a4 have been described, but the biological role of PGC-1a2 and a3 remains elusive. Here we show that different PGC-1a 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-1a isoform, we were able to identify a large number of previously unknown PGC-1a2 and a3 target genes and pathways in skeletal muscle. In particular, PGC-1a2 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/RRM) is what determines the gene programs and splicing options modulated by each PGC-1a isoform. By using skeletal muscle-specific transgenics for PGC-1a1 and a4, we could validate in vivo splicing events observed in in vitro studies. These results show that alternative PGC-1a variants can affect target gene expression both quantitatively and qualitatively, and identify novel biological pathways under the control of this system of coactivators.

ORGANISM(S): Mus musculus

PROVIDER: GSE75448 | GEO | 2016/06/07

SECONDARY ACCESSION(S): PRJNA304309

REPOSITORIES: GEO