Abstract
Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of these dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation.
Highlights
Understanding living cells at a systemic level is an increasingly important challenge in biology and medicine [1,2,3,4,5]
We show that experimental facts, linking variations of decay rates observed between different cell-types of an organism to variations of the abundance of intra-cellular biochemical agents in these cell-types, correspond to (a) differences in the expressed genetic regulatory network, and (b) these differences can be controlled via decay rates of intracellular agents
The change from one sequence of active sets to another can be interpreted as the expression modes of different cell-types and we show that changes in decay rates of molecular species trigger switches between expression modes
Summary
Understanding living cells at a systemic level is an increasingly important challenge in biology and medicine [1,2,3,4,5]. GRN coordinate regulatory dynamics on all levels from cell-fate [6,7] to stress response [8,9,10]. Qualitative understanding of GRN structure is for instance obtained from promoter sequences [11,12,13], gene-expression profiling [14,15,16] or protein-protein interactions (proteome) [17]. The structure of a GRN, i.e. its topology, is given by the way nodes in the network are connected by links. It has been recognized that quantitative information is required to understand the complex dynamical properties of regulatory interactions in living cells [18,19], mainly because dynamics on interaction networks with identical topology still depends on the strength of interactions (links) between agents (nodes). Any model should adequately reproduce GRN dynamics and sufficiently exhibit systemic properties of the GRN, including (i) homeostasis, (ii) multi-stability, (iii) periodic dynamics, (iv) alternating activity, (v) self-organized critical dynamics (SOC) and (vi) differentiability
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