Takigawa-Imamura Hisako, Mochizuki Atsushi
Division of Theoretical Biology, National Institute for Basic Biology, 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
J Theor Biol. 2006 Jul 21;241(2):178-92. doi: 10.1016/j.jtbi.2005.11.013. Epub 2006 Jan 4.
Cyanobacteria are the simplest organisms known to exhibit circadian rhythms, which is the fundamental process of homeostasis adapting to daily environmental changes. The cyanobacterial clock gene products, KaiA, KaiB, and KaiC interact with each other, and regulate KaiC phosphorylation and kaiBC expression in a circadian fashion. Molecular genetic study recently proposed that KaiC protein may enhance and repress transcription of clock genes depending on KaiC's phosphorylation status, however, the precise mechanism is still unknown. We developed a mathematical model for the dynamics of cyanobacterial circadian rhythms focusing on the transcriptional regulation by KaiC. We investigated the model using numerical methods, and predicted the transcriptional regulation mechanism by KaiC. We searched for conditions for generating circadian oscillation and concluded that only two mechanisms of the transcriptional regulation are the possible pictures. One is the Transcriptional Repression Model where KaiC represses transcription of the clock genes after phosphorylation, and the other is the Transcriptional Activation Model where KaiC induces transcription after phosphorylation. The Transcriptional Repression Model includes self-repression similarly to the circadian oscillator models that have been proposed previously, and dynamical oscillation is easy to understand. However, the Transcriptional Activation Model does not include any direct repression in its interactive circuit, and is distinct from the previous ideas for circadian clocks. Subsequent computer simulation showed that the Transcriptional Activation Model explains most of the observed mutant phenotypes, and the Transcriptional Repression Model realizes only a half of them. It was also revealed that oscillations in the Transcriptional Activation Model is much more robust against the disruption by cell division or cell elongation than the Transcriptional Repression Model. It suggests that the Transcriptional Activation Model may reflect the essence of the actual transcriptional mechanism of the kai oscillator in cyanobacteria.
蓝藻是已知表现出昼夜节律的最简单生物体，昼夜节律是适应日常环境变化的稳态基本过程。蓝藻生物钟基因产物KaiA、KaiB和KaiC相互作用，并以昼夜节律的方式调节KaiC磷酸化和kaiBC表达。分子遗传学研究最近提出，KaiC蛋白可能根据其磷酸化状态增强或抑制生物钟基因的转录，然而，确切机制仍然未知。我们开发了一个关于蓝藻昼夜节律动态的数学模型，重点关注KaiC的转录调控。我们使用数值方法研究了该模型，并预测了KaiC的转录调控机制。我们寻找产生昼夜振荡的条件，并得出结论，只有两种转录调控机制是可能的情况。一种是转录抑制模型，其中KaiC在磷酸化后抑制生物钟基因的转录，另一种是转录激活模型，其中KaiC在磷酸化后诱导转录。转录抑制模型类似于先前提出的昼夜振荡器模型，包括自我抑制，动态振荡易于理解。然而，转录激活模型在其交互回路中不包括任何直接抑制，并且与先前关于生物钟的观点不同。随后的计算机模拟表明，转录激活模型解释了大多数观察到的突变体表型，而转录抑制模型只实现了其中的一半。还发现，转录激活模型中的振荡比转录抑制模型对细胞分裂或细胞伸长引起的破坏更具鲁棒性。这表明转录激活模型可能反映了蓝藻中kai振荡器实际转录机制的本质。
