The Research Institute for Time Studies, Yamaguchi University, 1677-1 Yoshida, Yamaguchi, Yamaguchi 753-8511, Japan.
Division of Animal Genetics, Laboratory Animal Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan; Division of Genome Engineering, Center for Experimental Medicine and Systems Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Cell Rep. 2022 Apr 19;39(3):110703. doi: 10.1016/j.celrep.2022.110703.
The current model of the mammalian circadian clock describes cell-autonomous and negative feedback-driven circadian oscillation of Cry and Per transcription as the core circadian rhythm generator. However, the actual contribution of this oscillation to circadian rhythm generation remains undefined. Here we perform targeted disruption of cis elements indispensable for cell-autonomous Cry oscillation. Mice lacking overt cell-autonomous Cry oscillation show robust circadian rhythms in locomotor activity. In addition, tissue-autonomous circadian rhythms are robust in the absence of overt Cry oscillation. Unexpectedly, although the absence of overt Cry oscillation leads to severe attenuation of Per oscillation at the cell-autonomous level, circadian rhythms in Per2 accumulation remain robust. As a mechanism to explain this counterintuitive result, Per2 half-life shows cell-autonomous circadian rhythms independent of Cry and Per oscillation. The cell-autonomous circadian clock may therefore remain partially functional even in the absence of overt Cry and Per oscillation because of circadian oscillation in Per2 degradation.
目前哺乳动物生物钟的模型描述了细胞自主和负反馈驱动的 Cry 和 Per 转录的生物钟振荡，作为核心生物钟节律发生器。然而，这种振荡对生物钟节律产生的实际贡献仍然没有定义。在这里，我们对细胞自主 Cry 振荡所必需的顺式元件进行了靶向破坏。缺乏明显细胞自主 Cry 振荡的小鼠在运动活性中表现出稳健的生物钟节律。此外，在缺乏明显 Cry 振荡的情况下，组织自主的生物钟节律也是稳健的。出乎意料的是，尽管明显的 Cry 振荡缺失导致细胞自主水平的 Per 振荡严重减弱，但 Per2 积累的生物钟节律仍然稳健。作为解释这一反直觉结果的机制，Per2 的半衰期显示出细胞自主的生物钟节律，独立于 Cry 和 Per 振荡。因此，即使明显的 Cry 和 Per 振荡缺失，细胞自主生物钟时钟也可能保持部分功能，因为 Per2 降解存在生物钟振荡。
