A novel protein, CHRONO, functions as a core component of the mammalian circadian clock.
A novel protein, CHRONO, functions as a core component of the mammalian circadian clock.
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DOI：
10.1371/journal.pbio.1001839
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发表时间：
2014-04
期刊：
影响因子：
9.8
通讯作者：
Takumi T
中科院分区：
文献类型：
--
作者：
Goriki A;Hatanaka F;Myung J;Kim JK;Yoritaka T;Tanoue S;Abe T;Kiyonari H;Fujimoto K;Kato Y;Todo T;Matsubara A;Forger D;Takumi T
两项独立的研究，其中一项使用了计算方法，确定了CHRONO，一种调节昼夜转录因子活性并改变小鼠昼夜行为的基因。昼夜节律是由生物钟基因组成的负、正遗传反馈回路系统控制的。虽然许多基因都与这些反馈回路有关，但目前还不清楚我们目前的时钟基因清单是否详尽。我们最近通过对BMAL 1在E-box上的结合进行全基因组分析，将Chrono确定为一种稳健的循环转录物。在这里，我们探讨了Chrono在细胞计时中的作用。值得注意的是，E-box周围的内源性CHRONO占据显示出与BMAL 1反相的昼夜节律振荡。Chrono的过表达以组蛋白去乙酰化酶（HDAC）依赖性方式导致BMAL 1-CLOCK活性的抑制。Chrono（包括Avp神经元特异性敲除（KO）小鼠）的体内功能丧失研究显示出较长的昼夜节律运动活动期。Chrono KO还改变了核心时钟基因的表达，并损害了生物钟对压力的反应。CHRONO与糖皮质激素受体形成复合物并介导糖皮质激素反应。我们的综合研究突出了一个以前未被认识到的时钟组成部分，一个未知的负昼夜节律反馈回路，独立于另一个负调节因子Cry 2，并整合了行为应激和表观遗传控制，以实现时钟的有效代谢整合。生物钟在调节生物体的生物时间节律中具有基础作用，并且其由正反馈和负反馈调节环组成的分子回路紧密控制。虽然组成这个电路的许多时钟基因已经被确定，但仍然缺少一些关键组件。在这里，我们表征的昼夜节律基因命名为Chrono（Gm 129），并表明它的功能作为一个转录抑制负反馈回路中的哺乳动物时钟。Chrono与时钟基因的调控区结合，其占据率以昼夜节律的方式振荡。Chrono敲除和Avp神经元特异性敲除小鼠显示出更长的昼夜节律周期和改变的核心时钟基因表达。我们发现，Chrono介导的抑制涉及通过表观遗传机制抑制BMAL 1-CLOCK活性，并调节由行为应激引发的代谢途径。我们的研究表明，Chrono功能作为一个时钟阻遏物，并揭示了其功能的分子机制。
Two independent studies, one of them using a computational approach, identified CHRONO, a gene shown to modulate the activity of circadian transcription factors and alter circadian behavior in mice. Circadian rhythms are controlled by a system of negative and positive genetic feedback loops composed of clock genes. Although many genes have been implicated in these feedback loops, it is unclear whether our current list of clock genes is exhaustive. We have recently identified Chrono as a robustly cycling transcript through genome-wide profiling of BMAL1 binding on the E-box. Here, we explore the role of Chrono in cellular timekeeping. Remarkably, endogenous CHRONO occupancy around E-boxes shows a circadian oscillation antiphasic to BMAL1. Overexpression of Chrono leads to suppression of BMAL1–CLOCK activity in a histone deacetylase (HDAC) –dependent manner. In vivo loss-of-function studies of Chrono including Avp neuron-specific knockout (KO) mice display a longer circadian period of locomotor activity. Chrono KO also alters the expression of core clock genes and impairs the response of the circadian clock to stress. CHRONO forms a complex with the glucocorticoid receptor and mediates glucocorticoid response. Our comprehensive study spotlights a previously unrecognized clock component of an unsuspected negative circadian feedback loop that is independent of another negative regulator, Cry2, and that integrates behavioral stress and epigenetic control for efficient metabolic integration of the clock. The circadian clock has a fundamental role in regulating biological temporal rhythms in organisms, and it is tightly controlled by a molecular circuit consisting of positive and negative regulatory feedback loops. Although many of the clock genes comprising this circuit have been identified, there are still some critical components missing. Here, we characterize a circadian gene renamed Chrono (Gm129) and show that it functions as a transcriptional repressor of the negative feedback loop in the mammalian clock. Chrono binds to the regulatory region of clock genes and its occupancy oscillates in a circadian manner. Chrono knockout and Avp-neuron-specific knockout mice display longer circadian periods and altered expression of core clock genes. We show that Chrono-mediated repression involves the suppression of BMAL1–CLOCK activity via an epigenetic mechanism and that it regulates metabolic pathways triggered by behavioral stress. Our study suggests that Chrono functions as a clock repressor and reveals the molecular mechanisms underlying its function.
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DOI：
10.1073/pnas.0604511103
发表时间：
2006-07-11
影响因子：
11.1
作者：
Gallego, Monica;Eide, Erik J.;Forger, Daniel B.
通讯作者：
Forger, Daniel B.
影响因子：
3.5
作者：
Kim, J. K.;Forger, D. B.;Walton, K. M.
通讯作者：
Walton, K. M.
影响因子：
16.8
作者：
Duong HA;Weitz CJ
通讯作者：
Weitz CJ
影响因子：
13.9
作者：
Mohawk JA;Green CB;Takahashi JS
通讯作者：
Takahashi JS
影响因子：
64.8
作者：
Lamia, Katja A.;Papp, Stephanie J.;Yu, Ruth T.;Barish, Grant D.;Uhlenhaut, N. Henriette;Jonker, Johan W.;Downes, Michael;Evans, Ronald M.
通讯作者：
Evans, Ronald M.