A Unified Genomic Mechanism of Cell-Fate Change

International Journal of Molecular Sciences

Herein, we provide a brief overview of complex systems theory approaches to investigate the genomic mechanism of cell-fate changes. Cell trajectories across the epigenetic landscape, whether in development, environmental responses, or disease progression, are controlled by extensively coordinated genome-wide gene expression changes. The elucidation of the mechanisms underlying these coherent expression changes is of fundamental importance in cell biology and for paving the road to new therapeutic approaches. In previous studies, we pointed at dynamic criticality as a plausible characteristic of genome-wide transition dynamics guiding cell fate. Whole-genome expression develops an engine-like organization (genome engine) in order to establish an autonomous dynamical system, capable of both homeostasis and transition behaviors. A critical set of genes behaves as a critical point (CP) that serves as the organizing center of cell-fate change. When the system is pushed away from homeosta...

Biophysics Reviews, 2021

The human DNA molecule is a 2 meters long polymer collapsed into the micrometer space of the cell nucleus. This simple consideration rules out any ‘Maxwell demon’- like explanation of regulation in which a single regulatory molecule (e.g., a transcription factor) finds autonomously its way to the particular target gene whose expression must be repressed or enhanced. A gene-by-gene regulation is still more contrasting with physical reality when in presence of cell state transitions involving the contemporary expression change of thousands of genes. This state of affair asks for a statistical mechanics inspired approach where specificity arises from a selective unfolding of chromatin driving the rewiring of gene expression pattern. The arising of ‘expression waves’ marking state transitions related to chromatin structural reorganization through self-organized critical control (SOC) of whole genome expression will be described in the present paper. We adopt as model system the gene expression time course of a cancer cell (MCF-7) population exposed to an efficient (HRG) stimulus causing a state transition in comparison to an ineffective (EGF) stimulus. The obtained results will be put into the perspective of biological adaptive systems living on the ‘edge of chaos’.

Background A fundamental issue in bioscience is to understand the underlying mechanism of the dynamic control of genome-wide expression through the complex temporal-spatial self-organization of the genome regulating cell fate change. We address this issue by elucidating a physically motivated self-organizing mechanism. Principal Findings Building 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 population and single cell levels. The novel findings are: i) Mechanism of cell fate changes: A sandpile-type critical transition self-organizes overall expression into a few transcription response domains (critical states). Cell fate change occurs by means of a dissipative pulse-like global perturbation in self-organization through the erasure of an initial-state critical behaviors (criticality). Most notably, reprogramming of the 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) Perturbation mechanism of SOC controls: Global perturbations of the SOC controls involve the temporal regulation of critical states. Elucidation of the dynamic interaction of critical states in terminal cell fates reveals that sub-critical states (ensembles of genes for which expression undergoes only very limited changes during the process) act as a ‘source’ to sustain global perturbations, whereas super-critical states (ensembles of genes for which expression varies greatly) behave as a ‘sink’ to form a dominant cyclic state-flux with sub-critical states through the cell nuclear environment. Conclusion and Significance The ‘whole-genome’ level of gene expression regulation, where the collective behavior of low-variance genes plays a central role in genome-wide self-organization, complements the microscopic gene-by-gene fine tuning, and represents a still largely unexplored thermodynamically regulated mechanism responsible for massive genome expression reprogramming

In our current studies on whole genome expression in several biological processes, we have demonstrated the actual existence of self-organized critical control (SOC) of gene expression at both population and single cell level. SOC allows for cell-fate change by critical transition encompassing the entire genome expression that, in turn, is partitioned into distinct response domains (critical states). In this paper, we go more in depth into the elucidation of SOC control of genome expression focusing on the determination of critical point (CP) and associated distinct critical states in single-cell genome expression. This leads us to the proposal of a potential universal model with genome-engine mechanism for cell-fate change. Our findings suggest that the CP is fixed point in terms of temporal expression variance, where the CP (set of critical genes) becomes active (ON) for cell-fate change ('super-critical' in genome-state) or else inactive (OFF) state ('sub-critical' in genome-state); this may lead to a novel scenario of the cell-fate control through activating or inactivating CP.

Background A 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 Findings Building 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.

Understanding the basic mechanism of the spatio-temporal self-control of genome-wide gene expression engaged with the complex epigenetic molecular assembly is one of major challenges in current biological science. In this study, the genomewide dynamical profile of gene expression was analyzed for MCF-7 breast cancer cells induced by two distinct ErbB receptor ligands: epidermal growth factor (EGF) and heregulin (HRG), which drive cell proliferation and differentiation, respectively. We focused our attention to elucidate how global genetic responses emerge and to decipher what is an underlying principle for dynamic self-control of genome-wide gene expression. The whole mRNA expression was classified into about a hundred groups according to the root mean square fluctuation (rmsf). These expression groups showed characteristic timedependent correlations, indicating the existence of collective behaviors on the ensemble of genes with respect to mRNA expression and also to temporal changes in expression. All-or-none responses were observed for HRG and EGF (biphasic statistics) at around 10-20 min. The emergence of time-dependent collective behaviors of expression occurred through bifurcation of a coherent expression state (CES). In the ensemble of mRNA expression, the self-organized CESs reveals distinct characteristic expression domains for biphasic statistics, which exhibits notably the presence of criticality in the expression profile as a route for genomic transition. In time-dependent changes in the expression domains, the dynamics of CES reveals that the temporal development of the characteristic domains is characterized as autonomous bistable switch, which exhibits dynamic criticality (the temporal development of criticality) in the genome-wide coherent expression dynamics. It is expected that elucidation of the biophysical origin for such critical behavior sheds light on the underlying mechanism of the control of whole genome.

A statistical mechanical mean-field approach to the temporal development of biological regulation provides a phenomenological, but basic description of the dynamical behavior of genome expression in terms of autonomous self-organization with a critical transition (Self-Organized Criticality: SOC). This approach reveals the basis of self-regulation/organization of genome expression, where the extreme complexity of living matter precludes any strict mechanistic approach. The self-organization in SOC involves two critical behaviors: scaling-divergent behavior (genome avalanche) and sandpile-type critical behavior. Genome avalanche patterns—competition between order (scaling) and disorder (divergence) reflect the opposite sequence of events characterizing the self-organization process in embryo development and helper T17 terminal cell differentiation, respectively. On the other hand, the temporal development of sandpile-type criticality (the degree of SOC control) in mouse embryo suggests the existence of an SOC control landscape with a critical transition state (i.e., the erasure of zygote-state criticality). This indicates that a phase transition of the mouse genome before and after reprogramming (immediately after the late 2-cell state) occurs through a dynamical change in a control parameter. This result provides a quantitative open-thermodynamic appreciation of the still largely qualitative notion of the epigenetic landscape. Our results suggest: (i) the existence of coherent waves of condensation/de-condensation in chromatin, which are transmitted across regions of different gene-expression levels along the genome; and (ii) essentially the same critical dynamics we observed for cell-differentiation processes exist in overall RNA expression during embryo development, which is particularly relevant because it gives further proof of SOC control of overall expression as a universal feature.

Preprint, 2020

Through our studies on whole genome regulation, we have demonstrated the existence of self-organized critical control (SOC) of whole gene expression-genomic self-organization mechanism through the emergence of a critical point (CP) at both the cell population and single cell level. In this paper, based on HRG and EGF-stimulated MCF-7 breast-cancer cell line, we shed light on the origin of critical transitions stemming from coordinated chromatin remodeling. In so doing, we validated the core of the SOC control mechanism through the application of a non-linear signal analysis technique (Recurrence Quantification Analysis: RQA), and of Principal Component Analysis (PCA). The main findings were: 1. Transcriptional co-regulation follows a strong and invariant exponential decay as between gene spacing along the chromosome is increased. This shows that the co-regulation occurs on a mainly positional basis reflecting local chromatin organization. 2. There are two main fluctuation modes on the top of the cell-kind specific gene expression values spanning the entire genome expression. These modes establish an autonomous genomic critical control system (genome-engine) through the activation of the CP for cell-fate guiding critical transitions revealed by SOC analysis. The elucidation of the link between spatial position on chromosome and co-regulation together with the identification of specific locations on the genome devoted to the generalization of All rights reserved. No reuse allowed without permission. (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

2024

Phenotype transitions occur in many biological processes such as differentiation and reprogramming. A fundamental question is how cells coordinate switching of gene expression clusters. By analyzing single-cell RNA sequencing data within the framework of transition path theory, we studied the genome-wide expression program switching in five different cell transition processes. For each process we reconstructed a reaction coordinate describing the transition progression, and we inferred the gene regulatory network along this reaction coordinate. In all processes we observed a common pattern: the overall effective number and strength of regulation between different communities increase first and then decrease. This change is accompanied by similar changes in gene regulatory network frustration-defined as the overall conflict between the regulation received by genes and their expression states. Complementing previous studies suggesting that biological networks are modularized to contain perturbation effects locally, our analyses on the five cell transition processes likely reveal a general principle: during a cell phenotypic transition, intercommunity interactions increase to concertedly coordinate global gene expression reprogramming and canalize to specific cell phenotype, as Waddington visioned.

PloS one, 2015

The underlying mechanism of dynamic control of the genome-wide expression is a fundamental issue in bioscience. We addressed it in terms of phase transition by a systemic approach based on both density analysis and characteristics of temporal fluctuation for the time-course mRNA expression in differentiating MCF-7 breast cancer cells. In a recent work, we suggested criticality as an essential aspect of dynamic control of genome-wide gene expression. Criticality was evident by a unimodal-bimodal transition through flattened unimodal expression profile. The flatness on the transition suggests the existence of a critical transition at which up- and down-regulated expression is balanced. Mean field (averaging) behavior of mRNAs based on the temporal expression changes reveals a sandpile type of transition in the flattened profile. Furthermore, around the transition, a self-similar unimodal-bimodal transition of the whole expression occurs in the density profile of an ensemble of mRNA ex...