Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Nature. 2011 Dec 14;480(7378):552-6. doi: 10.1038/nature10700.
Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling. However, mechanisms that logically explain the coordination of nuclear hormone receptors and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in cryptochrome-deficient livers. These results reveal a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.
哺乳动物的新陈代谢具有高度的昼夜节律性，涉及核激素受体的主要激素回路显示出相互关联的昼夜循环。然而，逻辑上解释核激素受体和时钟协调的机制还知之甚少。在这里，我们表明，两种昼夜节律共调节剂，隐花色素 1 和 2，以配体依赖的方式与糖皮质激素受体相互作用，并在小鼠胚胎成纤维细胞中全局改变糖皮质激素的转录反应：隐花色素缺乏大大降低了基因抑制作用，并使地塞米松诱导的基因数量增加了约两倍，这表明隐花色素广泛反对糖皮质激素受体的激活并促进抑制作用。在小鼠中，隐花色素 1 和/或 2 的遗传缺失导致葡萄糖不耐受和循环皮质酮水平持续升高，这表明下丘脑-垂体-肾上腺轴的抑制作用降低，同时肝脏中的糖皮质激素反式激活增加。在基因组水平上，隐花色素 1 和 2 以激素依赖的方式与磷酸烯醇丙酮酸羧激酶 1 启动子中的糖皮质激素反应元件结合，并且在隐花色素缺陷的肝脏中，磷酸烯醇丙酮酸羧激酶 1 基因的地塞米松诱导转录显著增加。这些结果揭示了一种特定的机制，通过该机制，隐花色素将时钟和受体靶基因的活性与正常代谢稳态的复杂基因组回路联系起来。
