A feedback loop of conditionally stable circuits drives the cell cycle from checkpoint to checkpoint

Abstract

We perform logic-based network analysis on a model of the mammalian cell cycle. This model is composed of a Restriction Switch driving cell cycle commitment and a Phase Switch driving mitotic entry and exit. By generalizing the concept of stable motif, i.e., a self-sustaining positive feedback loop that maintains an associated state, we introduce the concept of a conditionally stable motif, the stability of which is contingent on external conditions. We show that the stable motifs of the Phase Switch are contingent on the state of three nodes through which it receives input from the rest of the network. Biologically, these conditions correspond to cell cycle checkpoints. Holding these nodes locked (akin to a checkpoint-free cell) transforms the Phase Switch into an autonomous oscillator that robustly toggles through the cell cycle phases G1, G2 and mitosis. The conditionally stable motifs of the Phase Switch Oscillator are organized into an ordered sequence, such that they serially stabilize each other but also cause their own destabilization. Along the way they channel the dynamics of the module onto a narrow path in state space, lending robustness to the oscillation. Self-destabilizing conditionally stable motifs suggest a general negative feedback mechanism leading to sustained oscillations.

A Guard Cell Abscisic Acid (ABA) Network Model That Captures the Stomatal Resting State

“…This work and our previous research on stable motifs (Zañudo and Albert, 2013;Steinway et al, 2014;Albert et al, 2017;Zanudo and Albert, 2015;Maheshwari et al, 2019;Rozum and Albert, 2018;Gan and Albert, 2018;Deritei et al, 2019) contributes to the broader field of investigation that connects positive feedback loops, multistability, cell fates and phenotypes (Thomas and Ari, 1990;Huang, 2007;Hari et al, 2020). Specifically, single or intersecting positive feedback loops form stable motifs or conditionally stable motifs.…”

“…Our work suggests a mechanism of cellular plasticity (phenotype switching): destabilization of the conditionally stable motif that underlies the phenotype by deactivating its condition. As seen in previous work (Deritei et al, 2019), stable motifs that are condition-free within the context of one model can become conditionally stable motifs in a broader model that encompasses the original model but includes more regulators and processes.…”

“…This advances our understanding of node oscillations in the context of a biological system modeled as a Boolean network. Seeking motivation from recent work (Deritei et al, 2019), we also identify conditionally stable and conditional oscillating motifs and differentiate them from their condition-free counterparts.…”

“…Some of these secondary stable motifs are dependent on certain conditions such as the prior stabilization of a node. For this reason, they are called conditionally stable motifs (see Section "Stable Motifs and Oscillating Motifs" and Deritei et al, 2019). The ABA-induced closure network also contains a negative feedback loop formed by the nodes Ca 2+…”

“…A weaker version of stable motifs was defined by Deritei et al (2019) and named conditionally stable motif. A conditionally stable motif is a consistent, strongly connected component of the expanded network that is not composite closed.…”