Abstract
BackgroundThe 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.MethodologyIn 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 expression. These singular and scaling behaviors identify the transition as the expression phase transition driven by self-organized criticality (SOC).Principal FindingsEmergent properties of SOC through a mean field approach are revealed: i) SOC, as a form of genomic phase transition, consolidates distinct critical states of expression, ii) Coupling of coherent stochastic oscillations between critical states on different time-scales gives rise to SOC, and iii) Specific gene clusters (barcode genes) ranging in size from kbp to Mbp reveal similar SOC to genome-wide mRNA expression and ON-OFF synchronization to critical states. This suggests that the cooperative gene regulation of topological genome sub-units is mediated by the coherent phase transitions of megadomain-scaled conformations between compact and swollen chromatin states.Conclusion and SignificanceIn summary, our study provides not only a systemic method to demonstrate SOC in whole-genome expression, but also introduces novel, physically grounded concepts for a breakthrough in the study of biological regulation.
Highlights
Inside living cells, a large number of molecular species (DNA, RNA, proteins, and metabolites) interact with each other in response to environmental stimuli
The scenario of transition between different symmetries found on the nrmsf suggests that a phase transition is expected to occur through a temporally invariant flattened energy profile; critical point (CP) of the transition should exist around a point at which up- and downregulated expression is balanced, i.e., the change in expression between different time points is zero
Global phase transition with a critical behavior in gene expression dynamics through a mean field approach was revealed in the early stress-like response to growth factors of the MCF-7 breast cancer cell line
Summary
A large number of molecular species (DNA, RNA, proteins, and metabolites) interact with each other in response to environmental stimuli. It is intriguing to consider how cells can select specific pathways, such as differentiation or immune response, out of the vast number of combinatorial possibilities arising from complex multi-molecular interactions. This robust organization goes hand-in-hand with an extreme sensitivity to specific stimuli: e.g., in mammalian stem cells, a few key transcription factors, such as Oct, Sox, and Nanog or Yamanaka’s factors in iPS cells, coordinate the expression of thousands of genes [1,2,3]. 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
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