Stochastic epigenetic dynamics of gene switching

Abstract

Epigenetic modifications of histones crucially affect the eukaryotic gene activity, while the epigenetic histone state is largely determined by the binding of specific factors such as the transcription factors (TFs) to DNA. Here, the way how the TFs and the histone state are dynamically correlated is not obvious when the TF synthesis is regulated by the histone state. This type of feedback regulatory relations are ubiquitous in gene networks to determine cell fate in differentiation and other cell transformations. To gain insights into such dynamical feedback regulations, we theoretically analyze a model of epigenetic gene switching by extending the Doi-Peliti operator formalism of reaction kinetics to the problem of coupled molecular processes. The spin-1 and spin-1/2 coherent state representations are introduced to describe stochastic reactions of histones and binding/unbinding of TF in a unified way, which provides a concise view of the effects of timescale difference among these molecular processes; even in the case that binding/unbinding of TF to/from DNA are adiabatically fast, the slow nonadiabatic histone dynamics give rise to a distinct circular flow of the probability flux around basins in the landscape of the gene state distribution, which leads to hysteresis in gene switching. In contrast to the general belief that the change in the amount of TF precedes the histone state change, the flux drives histones to be modified prior to the change in the amount of TF in the self-regulating circuits. The flux-landscape analyses shed light on the nonlinear nonadiabatic mechanism of epigenetic cell fate decision making.