Single-Cell Reprogramming in Mouse Embryo Development through a Critical Transition State

Abstract

Our previous work on the temporal development of the genome-expression profile in single-cell early mouse embryo indicated that reprogramming occurs via a critical transition state, where the critical-regulation pattern of the zygote state disappears. In this report, we unveil the detailed mechanism of how the dynamic interaction of thermodynamic states (critical states) enables the genome system to pass through the critical transition state to achieve genome reprogramming right after the late 2-cell state. Self-organized criticality (SOC) control of overall expression provides a snapshot of self-organization and explains the coexistence of critical states at a certain experimental time point. The time-development of self-organization is dynamically modulated by changes in expression flux between critical states through the cell nucleus milieu, where sequential global perturbations involving activation-inhibition of multiple critical states occur from the middle 2-cell to the 4-cell state. Two cyclic fluxes act as feedback flow and generate critical-state coherent oscillatory dynamics. Dynamic perturbation of these cyclic flows due to vivid activation of the ensemble of low-variance expression (sub-critical state) genes allows the genome system to overcome a transition state during reprogramming. Our findings imply that a universal mechanism of long-term global RNA oscillation underlies autonomous SOC control, and the critical gene ensemble at a critical point (CP) drives genome reprogramming. Identification of the corresponding molecular players will be essential for understanding single-cell reprogramming.

Cell-Fate Determination from Embryo to Cancer Development: Genomic Mechanism Elucidated

“…A mature mammalian somatic cell can reprogram its state (and consequently acquire a very different gene expression profile) through a few reprogramming stimuli [ In our previous studies [Tsuchiya, M., et al, 2014[Tsuchiya, M., et al, -2017Giuliani, A., et al, 2018], we have demonstrated the existence of self-organization in whole genome expression at both the population and single cell level that constitutes a 'physically motivated' alternative to the genespecific regulation. The mechanism of self-organization eliminates massive changes in the expression profile through the genome reprogramming inside a small and highly packed cell nucleus.…”

“…Coherent behavior (i.e., CM dynamics) emerges in stochastic expression (coherent-stochastic behavior) in each critical state. These coherent behaviors exhibit a universal genome-engine mechanism [Tsuchiya, M., et al, 2016[Tsuchiya, M., et al, , 2017 for SOC-control of genome expression; the subcritical state (ensemble of low-expression variance genes) is a generator that sustains the SOC control forming a dominant expression cyclic flux between sub-and super-critical (highexpression variance genes) states through the cell nuclear environment. sorted and grouped according to fold-change in expression between two different time points (e.g., between t = 0 and t =10min).…”

Self-Organized Critical Control of Genome Expression: Novel Scenario on Cell-Fate Decision

“…A mammalian mature stem cell can reprogram its state to acquire a very different gene expression profile through a few reprogramming stimuli [ In our studies [Tsuchiya, M., et al, 2014[Tsuchiya, M., et al, -2017Giuliani, A., et al, 2018], we have demonstrated the existence of self-organization in whole genome expression at both population and single cell level. A fundamental issue is to elucidate the mechanism of the self-organization at the 'whole genome' level of gene-expression regulation that is responsible for massive changes in the expression profile through the genome reprogramming inside a small and highly packed cell nucleus.…”

“…suggests that reprogramming occurs after the memory of initial state of the CP (e.g., zygote state) is lost (i.e., after the temporal CM correlation of the CP group pass zero-correlation: Figure 4B); the timing of this correlation event coincided with the timing of erasure of initialstate criticality for mouse and human embryo developments [Tsuchiya, M., et al, 2017;Giuliani, A., et al, 2018]. Furthermore, the timing of global perturbation on single-cell genome expression coincides with that of reprogramming (Figure 6B), which suggests that the activation of the CP occur when the initial-state CP memory is erased.…”

“…These CP behaviors reveal distinct response domains (critical states) in single-cell genome and associated coherent behavior (i.e., CM dynamics) emerged in stochastic expression (stochastic-coherent behavior) in each critical state. These coherent behaviors exhibit a universal genome-engine mechanism [Tsuchiya, M., et al, 2016[Tsuchiya, M., et al, , 2017 for SOC-control of genome expression (see Section IIB).…”