T3-mediated expression of PGC-1α via a far upstream located thyroid hormone response element

Thyroid hormone (T3) has a profound influence on normal development, differentiation and metabolism. T3 induces complex gene expression patterns raises the question of how these expression patterns might be regulated. Since the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) induces very similar cellular energy metabolic pathways, we investigated the molecular mechanism of T3 regulation of PGC-1α. PGC-1α is rapidly regulated by T3, both in vivo and in cell culture. Transient transfection experiments demonstrated binding of the thyroid hormone receptor (TR) to a response element located at −4 kb upstream of the transcriptional start site within the PGC-1α gene. Introducing of a single copy of the −4 kb TRE in a heterologous promoter context is sufficient to maintain T3 responsiveness. Chromatin immunoprecipitation analysis revealed increased histone acetylation upon stimulation of T3. Finally, TR binds the −4 kb TRE in electrophoretic mobility shift assays, identifying PGC-1α as a direct target of TR action. Since T3 directly regulates PGC-1α and PGC-1α coactivates liganded TR, we suggest an autoregulatory feed-forward loop of PGC-1α activation upon T3 treatment.