Self-Organizing Global Gene Expression Regulated through Criticality: Mechanism of the Cell-Fate Change

Abstract

BackgroundA fundamental issue in bioscience is to understand the mechanism that underlies the dynamic control of genome-wide expression through the complex temporal-spatial self-organization of the genome to regulate the change in cell fate. We address this issue by elucidating a physically motivated mechanism of self-organization.Principal FindingsBuilding upon transcriptome experimental data for seven distinct cell fates, including early embryonic development, we demonstrate that self-organized criticality (SOC) plays an essential role in the dynamic control of global gene expression regulation at both the population and single-cell levels. The novel findings are as follows: i) Mechanism of cell-fate changes: A sandpile-type critical transition self-organizes overall expression into a few transcription response domains (critical states). A cell-fate change occurs by means of a dissipative pulse-like global perturbation in self-organization through the erasure of initial-state critical behaviors (criticality). Most notably, the reprogramming of early embryo cells destroys the zygote SOC control to initiate self-organization in the new embryonal genome, which passes through a stochastic overall expression pattern. ii) Mechanism of perturbation of SOC controls: Global perturbations in self-organization involve the temporal regulation of critical states. Quantitative evaluation of this perturbation in terminal cell fates reveals that dynamic interactions between critical states determine the critical-state coherent regulation. The occurrence of a temporal change in criticality perturbs this between-states interaction, which directly affects the entire genomic system. Surprisingly, a sub-critical state, corresponding to an ensemble of genes that shows only marginal changes in expression and consequently are considered to be devoid of any interest, plays an essential role in generating a global perturbation in self-organization directed toward the cell-fate change.Conclusion and Significance‘Whole-genome’ regulation of gene expression through self-regulatory SOC control complements gene-by-gene fine tuning and represents a still largely unexplored non-equilibrium statistical mechanism that is responsible for the massive reprogramming of genome expression.

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

“…A complete erasure of the zygote state's criticality occurs after the late 2-cell state, such that a critical transition state should exist right after the late 2-cell state. Recently, we demonstrated that essentially the same critical-state dynamics that we observed for cell differentiation processes [4,6] are also present in overall RNA expression in Figure 7). Sandpile-type critical behaviors, which exhibit diverging up-and down-regulation at a critical point (CP: ln<nrmsf>~− 5.5), emerge in overall expression sorted and grouped according to the fold-change in expression (see stochastic resonance in [6]).…”

“…Recently, we demonstrated that essentially the same critical-state dynamics that we observed for cell differentiation processes [4,6] are also present in overall RNA expression in single-cell mouse embryo development, which presents further proof of SOC control as a universal characteristic [13]. Overall RNA expression and its dynamics exhibit typical features (genome avalanche and sandpile type criticality) of self-organized criticality (SOC) control in mouse embryo development; Figure 1 shows a genome avalanche, i.e., scaling-divergent behavior in a log-log-scale plot between expression and the temporal variance of expression (nrmsf ).…”

“…Overall RNA expression and its dynamics exhibit typical features (genome avalanche and sandpile type criticality) of self-organized criticality (SOC) control in mouse embryo development; Figure 1 shows a genome avalanche, i.e., scaling-divergent behavior in a log-log-scale plot between expression and the temporal variance of expression (nrmsf ). Figure 2 depicts the phenomena in Figure 1 along a time arrow, and clarifies early embryo development with a shift toward erasure of the previous organization pattern relative to the zygote state: sandpile-type criticality (critical behavior) of the zygote state survives at the early 2-cell state and disappears after the late 2-cell state to reach a stochastic pattern in the 4-cell state (linear pattern revealed in randomly shuffled overall expression: Figure S2 in [4]). …”

“…Since nrmsf is an order parameter [4][5][6], this reveals opposite orders of self-organization; similar scaling-divergent order for cell differentiation is also observed at a cell-population level in cancer cells [4,6]. Furthermore, since chromosomes exhibit fractal organization [14,15], this power law behavior may reveal a quantitative relation between the aggregation state of chromatin through nrmsf and the average expression of an ensemble of genes, which is opposite in embryo development and cell differentiation, and the existence of coherent waves of condensation/de-condensation in chromatin in cell development, which is transmitted from a region of low temporal expression (low nrmsf region) in reprogramming of the embryo genome, to high temporal expression (high nrmsf ) in terminal somatic cell differentiation.…”

“…In our previous studies, based on transcriptome experimental data for seven distinct cell fates [4], we recognized that a self-organized criticality (SOC) transition in whole-genome expression plays an essential role in the change in the genome expression state at both the population and single-cell levels (see Methods, for more details [4][5][6]). The essential points of SOC control of overall expression can be summarized as follows:…”