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Related Experiment Video

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Identification of MyoD Interactome Using Tandem Affinity Purification Coupled to Mass Spectrometry
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Multi-stability in cellular differentiation enabled by a network of three mutually repressing master regulators.

Atchuta Srinivas Duddu1, Sarthak Sahoo1,2, Souvadra Hati2

  • 1Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore, India.

Journal of the Royal Society, Interface
|September 30, 2020
PubMed
Summary

This study explores a toggle triad network motif, revealing it can create three distinct cell fates and hybrid states. This finding offers insights for designing multi-stable biological systems and synthetic biology applications.

Keywords:
T-cell differentiationmulti-stabilityphenotypic plasticitytoggle switchtoggle triad

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Area of Science:

  • Systems Biology
  • Synthetic Biology
  • Developmental Biology

Background:

  • Cellular decision-making relies on complex regulatory networks.
  • Toggle switch motifs, with two opposing regulators, drive binary cell fate choices.
  • Principles of coupled toggle switches are not well understood.

Purpose of the Study:

  • Investigate the dynamics of three coupled toggle switches (toggle triad) involving master regulators A, B, and C.
  • Determine the potential cell phenotypes generated by this toggle triad system.
  • Apply findings to understand T cell differentiation and inform synthetic biology.

Main Methods:

  • Computational simulations of a toggle triad network model.
  • Analysis of resulting cell phenotypes, including single and double positive states.
  • Application of the model to the differentiation of CD4+ T cells.

Main Results:

  • The toggle triad model predicts the co-existence of three 'single positive' cell phenotypes.
  • Hybrid or 'double positive' phenotypes can also coexist with single positive states.
  • Self-activation loops increase the frequency of 'double positive' states.
  • The model explains observed differentiation patterns in CD4+ T cells, including hybrid states.

Conclusions:

  • A toggle triad network can generate multi-stable cell fates, including hybrid phenotypes.
  • This provides a framework for understanding and designing tristable biological systems.
  • Findings have implications for synthetic biology and cellular reprogramming.