State Key Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Nat Cell Biol. 2019 Dec;21(12):1553-1564. doi: 10.1038/s41556-019-0420-4. Epub 2019 Nov 25.
Redox balance, an essential feature of healthy physiological steady states, is regulated by circadian clocks, but whether or how endogenous redox signalling conversely regulates clockworks in mammals remains unknown. Here, we report circadian rhythms in the levels of endogenous HO in mammalian cells and mouse livers. Using an unbiased method to screen for HO-sensitive transcription factors, we discovered that rhythmic redox control of CLOCK directly by endogenous HO oscillations is required for proper intracellular clock function. Importantly, perturbations in the rhythm of HO levels induced by the loss of p66, which oscillates rhythmically in the liver and suprachiasmatic nucleus (SCN) of mice, disturb the rhythmic redox control of CLOCK function, reprogram hepatic transcriptome oscillations, lengthen the circadian period in mice and modulate light-induced clock resetting. Our findings suggest that redox signalling rhythms are intrinsically coupled to the circadian system through reversible oxidative modification of CLOCK and constitute essential mechanistic timekeeping components in mammals.
氧化还原平衡是健康生理稳态的一个基本特征，它受生物钟的调节，但内源性氧化还原信号是否以及如何反过来调节哺乳动物的生物钟仍然未知。在这里，我们报告了内源性 HO 在哺乳动物细胞和小鼠肝脏中的水平存在昼夜节律。我们使用一种无偏的方法来筛选 HO 敏感的转录因子，发现内源性 HO 波动对 CLOCK 的直接节律性氧化还原控制是细胞内时钟功能正常所必需的。重要的是，由 p66 缺失引起的 HO 水平节律的改变，p66 在小鼠的肝脏和视交叉上核（SCN）中呈节律性波动，扰乱了 CLOCK 功能的节律性氧化还原控制，重新编程了肝转录组的波动，延长了小鼠的 circadian 周期，并调节了光诱导的时钟重置。我们的研究结果表明，氧化还原信号节律通过 CLOCK 的可逆氧化修饰与生物钟内在耦合，并构成了哺乳动物中基本的机制计时成分。
