Abstract
Cells generate phenotypic diversity both during development and in response to stressful and changing environments, aiding survival. Functionally vital cell fate decisions from a range of phenotypic choices are made by regulatory networks, the dynamics of which rely on gene expression and hence depend on the cellular energy budget (and particularly ATP levels). However, despite pronounced cell-to-cell ATP differences observed across biological systems, the influence of energy availability on regulatory network dynamics is often overlooked as a cellular decision-making modulator, limiting our knowledge of how energy budgets affect cell behaviour. Here, we consider a mathematical model of a highly generalisable, ATP-dependent, decision-making regulatory network, and show that cell-to-cell ATP variability changes the sets of decisions a cell can make. Our model shows that increasing intracellular energy levels can increase the number of supported stable phenotypes, corresponding to increased decision-making capacity. Model cells with sub-threshold intracellular energy are limited to a singular phenotype, forcing the adoption of a specific cell fate. We suggest that energetic differences between cells may be an important consideration to help explain observed variability in cellular decision-making across biological systems.
Highlights
Biological cells are faced with many decisions during their existence
As we are primarily concerned with the ATP dependence of gene expression, we modelled λ with a sigmoidal curve, yielding monotonically increasing rates as energy increases
Our model system generally exhibits dynamic behaviour that, starting from some initial condition (x1,0, x2,0), converges to a particular steady state characterised by values (x1, x2)
Summary
Biological cells are faced with many decisions during their existence. Genetically identical single cells in a population choose different phenotypic strategies for survival; genetically identical cells in developing multicellular organisms make decisions to follow different developmental pathways, and towards one of a diverse range of possible phenotypes. Waddington’s famous ‘epigenetic landscape’[14] pictures these developmental decisions as bifurcating channels that a developmental ‘ball’ can roll down to select different possible cell fate decisions; bifurcations in the landscape correspond to multistability, where a cell can support distinct, differentiated cell fates These repeated differentiation decisions allow, for example, human pluripotent stem cells to differentiate into all cell types in the human body[15,16], while modern technology allows reprogrammed cells to move back ‘up’ the epigenetic landscape[15,17]. These may include temperature changes, pH variability, nutrient limitation or, in some cases, the presence of antibiotics To overcome such environmental fluctuations, genetically homogeneous cells can generate phenotypic diversity in order to increase the probability that some members of the population will survive[19,20,21]. Transcription and translation require a substantial ATP budget[38,39], so there exists a core energy dependence in the dynamics of gene regulatory networks, potentially affecting the decisions supported by a given cell
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