title: Epigenetic Modifications of the PGC-1α Promoter during Exercise Induced Expression in Mice.
abstract: The transcriptional coactivator, PGC-1α, 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 13.7 kb upstream of the canonical PGC-1α promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1α mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1α transcripts. Although the β2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1α promoter B, it is not yet known what molecular changes occur to facilitate PGC-1α 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-1α promoter A, but that DNA methylation appeared to play no role in the exercise-induced activation of PGC-1α promoter B. The level of the activating histone mark H3K4me3 increased with exercise 2-4 fold across PGC-1α promoter B, but remained unaltered past the canonical PGC-1α transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1α isoforms.
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Lochmann
authors.affiliation: Parkinson's Center, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Ravindar R
authors.initials: RR
authors.lastname: Thomas
authors.affiliation: Parkinson's Center, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Neurology, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: James P
authors.initials: JP
authors.lastname: Bennett
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, United States of America; Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, United States of America.
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Taylor
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D051379:Mice; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D024363:Transcription Initiation Site
chemical_list: D006657:Histones; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors