Bilateral Feedback in Oscillator Model Is Required to Explain the Coupling Dynamics of Hes1 with the Cell Cycle

Abstract

Biological processes are governed by the expression of proteins, and for some proteins, their level of expression can fluctuate periodically over time (i.e., they oscillate). Many oscillatory proteins (e.g., cell cycle proteins and those from the HES family of transcription factors) are connected in complex ways, often within large networks. This complexity can be elucidated by developing intuitive mathematical models that describe the underlying critical aspects of the relationships between these processes. Here, we provide a mathematical explanation of a recently discovered biological phenomenon: the phasic position of the gene Hes1’s oscillatory expression at the beginning of the cell cycle of an individual human breast cancer stem cell can have a predictive value on how long that cell will take to complete a cell cycle. We use a two-component model of coupled oscillators to represent Hes1 and the cell cycle in the same cell with minimal assumptions. Inputting only the initial phase angles, we show that this model is capable of predicting the dynamic mitosis to mitosis behaviour of Hes1 and predicting cell cycle length patterns as found in real-world experimental data. Moreover, we discover that bidirectional coupling between Hes1 and the cell cycle is critical within the system for the data to be reproduced and that nonfixed asymmetry in the interactions between the oscillators is required. The phase dynamics we present here capture the complex interplay between Hes1 and the cell cycle, helping to explain nongenetic cell cycle variability, which has critical implications in cancer treatment contexts.