TY - JOUR
T1 - T3-mediated expression of PGC-1α via a far upstream located thyroid hormone response element
AU - Wulf, Anne
AU - Harneit, Angelika
AU - Kröger, Meike
AU - Kebenko, Maxim
AU - Wetzel, Marianne G.
AU - Weitzel, Joachim M.
N1 - Funding Information:
We are indebted to James Rhee and Christoph Handschin for kind gifts of plasmid DNA, to Danielle Gourdji for kind gift of rat pituitary GC cells and to Hans J. Seitz and Josef Köhrle for continued support during the project. The work was supported by a grant from the Deutsche Forschungsgemeinschaft (WE2458/3-2) to JMW.
PY - 2008/6/11
Y1 - 2008/6/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=43749088035&partnerID=8YFLogxK
U2 - 10.1016/j.mce.2008.01.017
DO - 10.1016/j.mce.2008.01.017
M3 - Journal articles
C2 - 18336995
AN - SCOPUS:43749088035
SN - 0303-7207
VL - 287
SP - 90
EP - 95
JO - Molecular and Cellular Endocrinology
JF - Molecular and Cellular Endocrinology
IS - 1-2
ER -
