Stochastic Dynamics of Gene Switches
Since cells are mesoscopic systems, fluctuations in biochemical reactions in vivo are not negligible. Reactions regulating gene expression are also largely fluctuating, so that the gene switching dynamics inevitably bears the large noise. We investigate the characteristics of noises in gene switches by developing statistical mechanical theories and stochastic simulations. Accuracy in the developing embryo is examined by considering the spatial diffusion of signal proteins to regulate the gene switching.
Y. Okabe-Oho, H. Murakami, S. Oho, and M. Sasai, "Stable, precise, and reproducible patterning of bicoid and hunchback molecules in the early Drosophila embryo", PLoS Comp. Biol. 5, e1000486_1-20 (2009).
M. Yoda, T. Ushikubo, W. Inoue & M. Sasai, "Roles of noise in single and coupled multiple genetic oscillators", J. Chem. Phys. 126(11) 115101-1-11 (2007).
Y. Okabe, Y. Yagi & M. Sasai, "Effects of the DNA state fluctuation on single-cell dynamics of self-regulating gene", J. Chem. Phys. 127, 105107 (2007).
Y. Okabe & M. Sasai. "Stable stochastic dynamics in yeast cell cycle", Biophys. J. 93, 3451-3459 (2007).
M. Sasai & P.G. Wolynes, "Stochastic Gene Expression as a Many Body Problem", Proc. Natl. Acad. Sci. USA 100(5) 2374-2379 (2003).
ES Cells and Reprogramming
With the suitable culture condition, embryonic stem (ES) cells can self-renew indefinitely by keeping the pluripotency. This homogenic population of ES cells, however, exhibits the large phenotypic heterogeneity: The expression level of Nanog and other marker factors largely fluctuate from cell to cell. We investigate the mechanism of this phenotypic fluctuation by simulating the core gene-network of ES cells. The calculated epigenetic landscapes suggest that this fluctuation helps the definite cell-fate decision of ES cells. The reprogramming process to iPS cells is analyzed by simulating the network model of gene switches.
M. Sasai, Y. Kawabata, K. Makishi, K. Itoh, and T. P. Terada, in preparation
Circadian Rhythm in the Kai System
In the ground-breaking discovery from the Kondo laboratory at Nagoya University, the stable temperature-compensated circadian rhythm was shown in the test tube containing three proteins KaiA, KaiB, and KaiC and ATP. The mechanism of oscillation of this Kai system remains still elusive and the role of ATP hydrolysis in KaiC seems the key issue to resolve the mystery of the Kai system. We investigate this problem by focusing on the stochastic dynamics of reactions and structural changes of Kai proteins.
T. Nagai, T. P. Terada, and M. Sasai, "Synchronizaion of circadian oscillation of phosphorylation level of KaiC in vitro", Biophys. J. 98: 2469-2477 (2010).
K. Eguchi, M. Yoda, T. P. Terada, and M. Sasai, "Mechanism of robust circadian oscillation of KaiC phosphorylation in vitro", Biophys. J. 95: 1773-1784 (2008).
M. Yoda, K. Eguchi, T. P. Terada, and M. Sasai, "Monomer-shuffling and allosteric transition in circadian oscillation of KaiC phosphorylation", PLoS ONE 2: e408 (2007).