Gene Networks of Fully Connected Triads with Complete Auto-Activation Enable Multistability and Stepwise Stochastic Transitions

Abstract

Fully-connected triads (FCTs), such as the Oct4-Sox2-Nanog triad, have been implicated as recurring transcriptional motifs embedded within the regulatory networks that specify and maintain cellular states. To explore the possible connections between FCT topologies and cell fate determinations, we employed computational network screening to search all possible FCT topologies for multistability, a dynamic property that allows the rise of alternate regulatory states from the same transcriptional network. The search yielded a hierarchy of FCTs with various potentials for multistability, including several topologies capable of reaching eight distinct stable states. Our analyses suggested that complete auto-activation is an effective indicator for multistability, and, when gene expression noise was incorporated into the model, the networks were able to transit multiple states spontaneously. Different levels of stochasticity were found to either induce or disrupt random state transitioning with some transitions requiring layovers at one or more intermediate states. Using this framework we simulated a simplified model of induced pluripotency by including constitutive overexpression terms. The corresponding FCT showed random state transitioning from a terminal state to the pluripotent state, with the temporal distribution of this transition matching published experimental data. This work establishes a potential theoretical framework for understanding cell fate determinations by connecting conserved regulatory modules with network dynamics. Our results could also be employed experimentally, using established developmental transcription factors as seeds, to locate cell lineage specification networks by using auto-activation as a cipher.

Cell population heterogeneity and evolution towards drug resistance in cancer: Biological and mathematical assessment, theoretical treatment optimisation

“…It is intended to represent at the cell population level cells on their way to differentiation from the stem-cell state as balls rolling down a scenery of bifurcating valleys, the last subdivisions of which end in fully differentiated states. It has been revisited by Sui Huang and colleagues in a series of articles [128,129,130,132,131,133,134,135,136,203,204], which link the bifurcations occurring between the valleys of the epigenetic landscape to bistable -or multistable [81] -switches in ordinary differential equations of systems biology representing the expression of antagonistic genes, such as PU.1 and GATA1 for the choice between myeloid and erythroid fates in the haematopoietic differentiation tree [46,111,136]. Sui Huang proposes, reversing the quote of Theodosius Dobzhansky [69], that "nothing in evolution makes sense except in the light of systems biology" [132].…”

Control of synthetic gene networks and its applications

“…On an intracellular level, GA (or the related Monte Carlo simulation) is often used to simulate stochastic fluctuations in transcriptional regulator numbers [24,61]. These types of simulations can be used to determine likelihood of state transitions under varying amounts of noise [52] or to thoroughly analyze the GRNs potential landscape under a single noise condition [56].…”

“…For example, Yao et al identified a minimal circuit to generate bistability from a simplified Rb-E2F network which regulates the initiation of DNA replication [79]. Faucon et al looked for instances of possible ways in which a three-gene network could exhibit multistability [52]. Additional work has been done to demonstrate the role that small motifs play in enhancing network stability [80].…”

Equilibrium switching and mathematical properties of nonlinear interaction networks with concurrent antagonism and self-stimulation

“…Self-stimulation is a common property of master switches in gene regulation and other biological signaling systems [22,17,23,24]. In fact, the CDM is a candidate model of biological switches that exhibit multi-stability (co-existence of multiple stable equilibria) [25][26][27][28][29]. At the ecological level, self-stimulation can be regarded as a characteristic of individuals or populations for increasing fitness and avoiding extinction.…”