Transcription Factor Tfe3 Directly Regulates Pgc-1alpha in Muscle.
The microphthalmia (MiT) family of transcription factors is an important mediator of metabolism. Family members Mitf and Tfeb directly regulate the expression of the master regulator of metabolism, peroxisome-proliferator activated receptor gamma coactivator-1 alpha (Pgc-1alpha), in melanomas and in the liver, respectively. Pgc-1alpha is enriched in tissues with high oxidative capacity and plays an important role in the regulation of mitochondrial biogenesis and cellular metabolism. In skeletal muscle, Pgc-1alpha affects many aspects of muscle functionally such as endurance, fiber-type switching, and insulin sensitivity. Tfe3 also regulates muscle metabolic genes that enhance insulin sensitivity in skeletal muscle. Tfe3 has not yet been shown to regulate Pgc-1alpha expression. Our results reported here show that Tfe3 directly regulates Pgc-1alpha expression in myotubes. Tfe3 ectopic expression induces Pgc-1alpha, and Tfe3 silencing suppresses Pgc-1alpha expression. This regulation is direct, as shown by Tfe3's binding to E-boxes on the Pgc-1alpha proximal promoter. We conclude that Tfe3 is a critical transcription factor that regulates Pgc-1alpha gene expression in myotubes. Since Pgc-1alpha coactivates numerous biological programs in diverse tissues, the regulation of its expression by upstream transcription factors such Tfe3 implies potential opportunities for the treatment of diseases where modulation of Pgc-1alpha expression may have important clinical outcomes.
Department of Dermatology, Cutaneous Biology Research Center (CBRC), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
Nunciada
N
Salma
Institute for Genomic Biology, CDMC Theme, Urbana, Illinois.|Department of Bioengineering, University of Illinois, Urbana, Illinois.|Department of Physics, University of Illinois, Urbana, Illinois.
Jun S
JS
Song
Cardiovascular Institute Perelman School of Medicine. University of Pennsylvania, Smilow Center for Translational Research, Philadelphia, Pennsylvania.
Zoltan
Z
Arany
Department of Dermatology, Cutaneous Biology Research Center (CBRC), Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts.
David E
DE
Fisher
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D063269:Mitochondrial Turnover / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; C068486:Tcfe3 protein, mouse