Journal
PHYSICAL BIOLOGY
Volume 14, Issue 3, Pages -Publisher
IOP PUBLISHING LTD
DOI: 10.1088/1478-3975/aa6f90
Keywords
multistability; cell-fate decision; toggle switch; self-activating toggle switch; coupling decision-making
Categories
Funding
- Physics Frontiers Center NSF [PHY-1427654]
- NSF [DMS-1361411, PHY-1605817]
- Cancer Prevention and Research Institute of Texas (CPRIT) [R1111]
- Gulf Coast Consortia on the Computational Cancer Biology Training Program (CPRIT) [RP170593]
- Division Of Mathematical Sciences
- Direct For Mathematical & Physical Scien [1361411] Funding Source: National Science Foundation
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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-(A, B) =(1, 0) or (0, 1)-and the third state corresponding to an 'undecided' stem-like state with similar levels of both A and B-(A, B) = (1/2,1/2). 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.
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