Reddy Akhilesh B, Maywood Elizabeth S, Karp Natasha A, King Verdun M, Inoue Yusuke, Gonzalez Frank J, Lilley Kathryn S, Kyriacou Charalambos P, Hastings Michael H
MRC Laboratory of Molecular Biology, Hills Road, Cambridge, Cabridgeshire, UK.
Hepatology. 2007 Jun;45(6):1478-88. doi: 10.1002/hep.21571.
Circadian control of physiology is mediated by local, tissue-based clocks, synchronized to each other and to solar time by signals from the suprachiasmatic nuclei (SCN), the master oscillator in the hypothalamus. These local clocks coordinate the transcription of key pathways to establish tissue-specific daily metabolic programs. How local transcriptomes are synchronized across the organism and their relative contribution to circadian output remain unclear. In the present study we showed that glucocorticoids alone are able to synchronize expression of about 60% of the circadian transcriptome. We propose that synchronization occurs directly by the action of glucocorticoids on a diverse range of downstream targets and indirectly by regulating the core clock genes mPer1, Bmal1, mCry1, and Dbp. We have identified the pivotal liver transcription factor, HNF4alpha, as a mediator of circadian and glucocorticoid-regulated transcription, showing that it is a key conduit for downstream targeting.
We have demonstrated that by orchestrating transcriptional cascades, glucocorticoids are able to direct synchronization of a diverse range of functionally important circadian genes.
生理节律的昼夜控制由局部的、基于组织的生物钟介导，这些生物钟通过来自下丘脑主振荡器视交叉上核（SCN）的信号相互同步并与太阳时间同步。这些局部生物钟协调关键途径的转录，以建立组织特异性的每日代谢程序。目前尚不清楚局部转录组如何在整个生物体中同步以及它们对昼夜节律输出的相对贡献。在本研究中，我们表明仅糖皮质激素就能使约60%的昼夜转录组表达同步。我们提出，同步直接通过糖皮质激素对多种下游靶点的作用发生，间接通过调节核心生物钟基因mPer1、Bmal1、mCry1和Dbp发生。我们已确定关键的肝脏转录因子HNF4α是昼夜节律和糖皮质激素调节转录的介质，表明它是下游靶向的关键通道。
我们已证明，通过协调转录级联反应，糖皮质激素能够直接使多种功能重要的昼夜节律基因同步。
