Transcriptional autoregulation by phosphorylated and non-phosphorylated KaiC in cyanobacterial circadian rhythms

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.