Operating principles of tristable circuits regulating cellular differentiation

Phys Biol. 2017 May 23;14(3):035007. doi: 10.1088/1478-3975/aa6f90.

Abstract

Many cell-fate decisions during embryonic development are governed by a motif comprised of two transcription factors (TFs) A and B that mutually inhibit each other and may self-activate. This motif, called as a self-activating toggle switch (SATS), can typically have three stable states (phenotypes)-two corresponding to differentiated cell fates, each of which has a much higher level of one TF than the other-[Formula: see text] or [Formula: see text]-and the third state corresponding to an 'undecided' stem-like state with similar levels of both A and B-[Formula: see text]. Furthermore, two or more SATSes can be coupled together in various topologies in different contexts, thereby affecting the coordination between multiple cellular decisions. However, two questions remain largely unanswered: (a) what governs the co-existence and relative stability of these three stable states? (b) What orchestrates the decision-making of coupled SATSes? Here, we first demonstrate that the co-existence and relative stability of the three stable states in an individual SATS can be governed by the relative strength of self-activation, external signals activating and/or inhibiting A and B, and mutual degradation between A and B. Simultaneously, we investigate the effects of these factors on the decision-making of two coupled SATSes. Our results offer novel understanding into the operating principles of individual and coupled tristable self-activating toggle switches (SATSes) regulating cellular differentiation and can yield insights into synthesizing three-way genetic circuits and understanding of cellular reprogramming.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Differentiation*
  • Cellular Reprogramming*
  • Embryonic Development / physiology*
  • Gene Regulatory Networks*
  • Models, Biological
  • Transcription Factors / metabolism*

Substances

  • Transcription Factors