Operating principles of tristable circuits regulating cellular differentiation

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.

Interconnected feedback loops among ESRP1, HAS2, and CD44 regulate epithelial-mesenchymal plasticity in cancer

“…miR-200/ZEB1 circuit without HAS2, CD44, and ESRP1) identified ZEB1 self-activation as a crucial link. Modulating the strength of self-activation significantly affected the range of SNAIL levels for which cells could acquire a stable hybrid E/M phenotype [25], consistent with observations for such feedback loops enabling three states [34,35].…”

Robustness and timing of cellular differentiation through population-based symmetry breaking

“…The observations that expression of mutually exclusive genetic markers distinguish the differentiated fates among each other and from the multilineage primed state have promoted the hypothesis that multistability on the level of single cells sets the dynamical basis for differentiation (Kauffman, 1969;Andrecut et al, 2011;Wang et al, 2011;Enver et al, 2009). The most common functional motif that accounts for bistability on a single cell level is a two-component genetic toggle-switch (Thomas, 1981;Cherry and Adler, 2000;Snoussi, 1998), whereas addition of self-activating loops (Huang et al, 2007;Bessonnard et al, 2014;Jia et al, 2017) gives rise to a third stable state -the multilineage primed co-expression state. Such single cell multistable circuits have been used to describe the Gata1/PU.1 switch that governs the lineage commitment in multipotent progenitor cells (Huang et al, 2007;Graf and Enver, 2009), the Cdx2/Oct4 switch in the differentiation of the totipotent embryo (Niwa et al, 2005), the T-bet/Gata3 switch in the specification of the T-helper cells (Huang, 2013) as well as the Gata6/Nanog switch in the branching process of inner cell mass (ICM) (Bessonnard et al, 2014;Chickarmane and Peterson, 2008).…”

“…It would be therefore formally correct to exploit the concept of multistability as a basis for differentiation only when this reflects the dynamics of the full communicating system. We therefore generated a paradigmatic multistability model where toggle switch with self-activation leads to tristability on the level of single cells (Jia et al, 2017), but also the dynamics of the coupled system (Eq. (2)) resulted in a tristable behavior (Fig.…”

“…Following (Jia et al, 2017) that demonstrated tristability on a single cell level, we introduced cell-cell communication to achieve tristability on a population level ( Figs. 3G and 3H) with the following equations: , λ B,B , n B,B , B 0…”

Phenotypic Plasticity and Cell Fate Decisions in Cancer: Insights from Dynamical Systems Theory

“…stem-like properties or tumor-initiation potential (54), and thus behave operationally as Cancer Stem Cells (CSCs) as observed in multiple solid tumors (55). The coupling between EMT and stemness is finely regulated.…”