In the human body, there are approximately two-hundred different cell types with diverse biological functions, all of which originate from a single zygote cell (fertilized egg cell of two gametes: sperm and egg). The cell state change (cell-fate change) from the zygote cell state involves on/off switching on thousands of functionally unique genes in a remarkably coordinated manner through the development.

However, it was still one of the daunting challenges to understand a genomic mechanism of how the cell-fate change involving the entire gene expression occurs to achieve the self-control of on/off switching for thousands of functionally unique genes in a small and highly packed cell nucleus.

In the paper ”Underlying Genomic Mechanism for Cell-Fate Change from Embryo to Cancer Development”, Masa Tsuchiya through forming an international collaboration with Alessandro Giuliani (Italy) and Kenichi Yoshikawa (Japan) investigated whole gene expression (Microarray and RNA-Seq data) and its dynamics to address the following fundamental questions:

i) Is there any underlying principle that self-regulates whole-genome expression?

ii) Does a universal mechanism exist to guide the self-organization so as to determine the change in the cell fate?

The team led by Masa has elucidated a potential universal genomic (expression) mechanism that underlies the cell-fate change from embryo to cancer development for both single cell and cell population, which is summarized as follows:

I) Systematic determination of critical point (CP) and critical states (distinct response domains): Whole gene expression (genome expression) is self-organized through the CP: super-critical state: (ensemble of) high temporal-variance gene expression; near-critical state: intermediate variance expression; sub-critical state: low variance expression.

II) Singular behaviors of the CP: The CP exhibits a clear transitional behavior, which is closely concerned with the intrinsic characteristics of the first-order phase transition inherent in genome sized DNA molecules. This suggests that the CP competes between the active (swelled or coil) and inactive (compact or globule) states to determine the cell-fate decision.

III) Genome-engine mechanism: The time-development of self-organization is dynamically modulated by exchanges in expression flux between critical states through the cell nucleus milieu. Surprisingly, a sub-critical state, an ensemble of genes that are considered to be devoid of any interest in biological studies dues to only marginal changes in expression, plays an essential role in generating a genome-engine – a dominant expression cyclic flux between the sub- and super-critical states through the cell nuclear milieu. Cell-fate change occurs through coherent perturbation (e.g., enhancement-suppression around the cell-fate change) on the genome-engine with the activation (ON) of the CP.

Going by the classical concept of self-organized critical control, the team noticed that the activation and inactivation of CP suggested that there might be another layer of a macro-state (genome state) composed of distinct micro-critical states, which was discovered by them. According to them, “the development of a theoretical foundation and elucidation of the underlying molecular mechanism for the autonomous critical control system in genome expression as revealed” in their findings “is expected to open new doors for a general control mechanism of the cell-fate change and genome computing”. Masa and the team have also expressed that the strong interaction among genes with extremely different expression variance and physiological roots push for a complete re-shaping of the present molecular – reductionist view of biological regulation. They have concluded affirming that the view of the genome acting as an integrated dynamical system is here to stay. The research conducted by the team is a valuable contribution to the field of bioscience.

Their work will act as a catalyst and will promote further research. Masa is the founder of SEIKO Life Science Laboratory, which is committed to the goal to support the development of breakthrough biomedical technologies. Masa Tsuchiya is a leading scientist and his research will certainly add merit to the war against cancer.

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