抄録
The logic of complex and dynamic biological networks such as circadian clocks is difficult to elucidate without (1) comprehensive identification of network structure, (2) prediction and validation based on quantitative measurement and perturbation of network behavior.First, we comprehensively determined the transcriptional regulatory circuits composed of 20 transcription factors, and three type of DNA elements including "morning" element (E-box), "day-time" element (D-box) and "night-time" element (RevErbA/ROR binding element, RRE)1,2. The following quantitative measurement and static perturbation of clock circuits revealed that E-box/E'-box regulation represents a topological and functional vulnerability in mammalian clocks2,3. Second, we synthetically implemented photo-responsiveness within mammalian cells by introducing a photoreceptor, melanopsin, and continuously monitored the effect of photo-perturbation on the state of cellular clocks. We report that the phase and amplitude of cellular clocks can be regulated by changing the timing and duration of light pulses. We reveal that a critical light pulse drives cellular clocks into a singularity behavior where robust circadian rhythmicity ce abolished after a certain stimulus. Theoretical analysis and subsequent single-cell-level observation predicts consistently and proves directly that desynchronization of individual cellular clocks underlies this singularity behavior4.Reference 1. Ueda, H.R. et al, Nature 418, 534-539 (2002). 2. Ueda, H.R. et al, Nat. Genet. 37, 187-192 (2005). 3. Sato T K, et al, Nat Genet. 38:312-9 (2006). 4. Ukai H, et al, Nat Cell Biol. 9, 1327–1334 (2007). [J Physiol Sci. 2008;58 Suppl:S32]
