Wulf Anne, Harneit Angelika, Kröger Meike, Kebenko Maxim, Wetzel Marianne G, Weitzel Joachim M
Zentrum für Experimentelle Medizin, Institut für Biochemie und Molekularbiologie I, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany.
Mol Cell Endocrinol. 2008 Jun 11;287(1-2):90-5. doi: 10.1016/j.mce.2008.01.017. Epub 2008 Feb 3.
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 gamma coactivator-1alpha (PGC-1alpha) induces very similar cellular energy metabolic pathways, we investigated the molecular mechanism of T3 regulation of PGC-1alpha. PGC-1alpha 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 -4kb upstream of the transcriptional start site within the PGC-1alpha gene. Introducing of a single copy of the -4kb 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 -4kb TRE in electrophoretic mobility shift assays, identifying PGC-1alpha as a direct target of TR action. Since T3 directly regulates PGC-1alpha and PGC-1alpha coactivates liganded TR, we suggest an autoregulatory feed-forward loop of PGC-1alpha activation upon T3 treatment.
甲状腺激素（T3）对正常发育、分化和代谢有着深远影响。T3诱导复杂的基因表达模式，这就引发了这些表达模式如何被调控的问题。由于转录共激活因子过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）诱导非常相似的细胞能量代谢途径，我们研究了T3对PGC-1α调控的分子机制。在体内和细胞培养中，PGC-1α都能被T3快速调控。瞬时转染实验表明甲状腺激素受体（TR）与位于PGC-1α基因转录起始位点上游-4kb处的一个反应元件结合。在异源启动子环境中引入单拷贝的-4kb甲状腺激素反应元件（TRE）足以维持对T3的反应性。染色质免疫沉淀分析显示，T3刺激后组蛋白乙酰化增加。最后，在电泳迁移率变动分析中TR与-4kb TRE结合，确定PGC-1α是TR作用的直接靶点。由于T3直接调控PGC-1α且PGC-1α共激活结合配体的TR，我们提出在T3处理后PGC-1α激活的一种自动调节前馈环。
