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Pluripotency gene network dynamics: System views from parametric analysis.

Ilya R Akberdin1,2,3, Nadezda A Omelyanchuk1,2, Stanislav I Fadeev2,4

  • 1Federal Research Center Institute of Cytology and Genetics SB RAS, Novosibirsk, Russia.

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This study revises the core gene network for mouse embryonic stem cells (ESCs), revealing four dynamical domains that may act as developmental checkpoints. Mathematical modeling highlights how network architecture influences pluripotency and differentiation.

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Area of Science:

  • Developmental Biology
  • Stem Cell Biology
  • Systems Biology

Background:

  • The core gene network regulating mouse embryonic stem cell (ESC) self-renewal and differentiation involves Oct4, Sox2, and Nanog.
  • Previous models emphasized positive feedback loops, but recent findings suggest negative Nanog autoregulation and potentially absent positive feedback from Nanog to Oct4/Sox2.

Purpose of the Study:

  • To investigate the dynamics of a revisited core gene regulatory circuit for ESCs.
  • To analyze how variations in Oct4/Sox2 activation and Nanog autorepression complexity affect model dynamics.
  • To explore the potential role of identified dynamical domains as developmental checkpoints.

Main Methods:

  • Mathematical modeling and thorough parametric analysis of the revisited core regulatory circuit.
  • Simulation of model dynamics under varying parameter strengths for Oct4/Sox2 activation and Nanog autorepression.
  • Investigation of system behavior, including steady states and oscillatory patterns.

Main Results:

  • Identified four distinct dynamical domains characterized by different numbers of stable and unstable steady states.
  • Demonstrated that parametric conditions can lead to oscillatory behavior, explaining cellular heterogeneity in ESC cultures.
  • Showed that incorporating positive feedback from Nanog to Oct4/Sox2 expands the parameter space for the naive ESC state, favoring pluripotency.

Conclusions:

  • The revisited core gene network model provides insights into developmental transitions between naïve and primed pluripotency.
  • The identified dynamical domains may represent critical checkpoints in ESC development.
  • Network architecture, particularly feedback loop configurations, significantly impacts ESC state stability and pluripotency maintenance.