Recently, Hao Ge and Sunney Xie groups proposed a new theory for stochastic phenotype transition of single cells, quantitatively describing how the switching rates among different gene states affect the transition rate between different phenotypes. The paper was published this February in Physical Review Letters.

Multiple phenotypic states often arise in a single cell with different gene-expression states that undergo transcription regulation with positive feedback. A single cell behaves stochastically with time as a consequence of gene expressions and biochemical regulations. The intrinsic stochasticity of cellular kinetics has two major origins: the stochastic gene state switching and copy-number fluctuations of proteins. The former is pertinent to the fact that there is only a single copy of DNA inside a typical cell that leads to stochastic productions of mRNA and protein, while the latter results from the low copy numbers of certain proteins.

Recent experiments show that, at least in E. coli, the gene state switching can be neither extremely slow nor exceedingly rapid as many previous theoretical treatments assumed. Rather, it is in the intermediate region which is difficult to handle mathematically. Under this condition, from a full chemical-master-equation description we derive a model in which the protein copy number, for a given gene state, follows a deterministic mean-field description while the protein-synthesis rates fluctuate due to stochastic gene state switching. The simplified kinetics yields a nonequilibrium landscape function, which, similar to the energy function for equilibrium fluctuation, provides the leading orders of fluctuations around each phenotypic state, as well as the transition rates between the two phenotypic states. This rate formula is analogous to Kramers’ theory for chemical reactions. The resulting behaviors are significantly different from the two limiting cases studied previously.

Their theory indicates that the stochastic nature of a single DNA molecule is essential for discrete phenotypic cellular states and their functions.

This research is funded by NSFC and MOE.

Citation:

Hao Ge, Hong Qian and X. Sunney Xie. Stochastic Phenotype Transition of a Single Cell in an Intermediate Region of Gene State Switching. Physical Review Letters, 114, 078101 (2015)

DOI: 10.1103/PhysRevLett.114.078101

http://journals.aps.org/prl/abstract/10.1103/PhysRevLett.114.078101