Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice

The transcriptional coactivator, PGC-1 alpha, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7kb upstream of the canonical PGC-1 alpha promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1 alpha mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1 alpha transcripts. Although the beta(2)-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1 alpha promoter B, it is not yet known what molecular changes occur to facilitate PGC-1 alpha promoter B activation following exercise. We sought to determine whether epigenetic modifications were involved in this exercise response in mouse skeletal muscle. We found that DNA hydroxymethylation correlated to increased basal mRNA levels from PGC-1 alpha promoter A, but that DNA methylation appeared to play no role in the exercise-induced activation of PGC-1 alpha promoter B. The level of the activating histone mark H3K4me3 increased with exercise 2-4 fold across PGC-1 alpha promoter B, but remained unaltered past the canonical PGC-1 alpha transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1 alpha isoforms.