A self-organized model for cell-differentiation based on variations of molecular decay rates

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 this 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.Comment: 16 pages, 5 figure

Time-delayed models of gene regulatory networks

We discuss different mathematical models of gene regulatory networks as relevant to the onset and development of cancer. After discussion of alternativemodelling approaches, we use a paradigmatic two-gene network to focus on the role played by time delays in the dynamics of gene regulatory networks. We contrast the dynamics of the reduced model arising in the limit of fast mRNA dynamics with that of the full model. The review concludes with the discussion of some open problems

Stable and unstable attractors in Boolean networks

Boolean networks at the critical point have been a matter of debate for many years as, e.g., scaling of number of attractor with system size. Recently it was found that this number scales superpolynomially with system size, contrary to a common earlier expectation of sublinear scaling. We here point to the fact that these results are obtained using deterministic parallel update, where a large fraction of attractors in fact are an artifact of the updating scheme. This limits the significance of these results for biological systems where noise is omnipresent. We here take a fresh look at attractors in Boolean networks with the original motivation of simplified models for biological systems in mind. We test stability of attractors w.r.t. infinitesimal deviations from synchronous update and find that most attractors found under parallel update are artifacts arising from the synchronous clocking mode. The remaining fraction of attractors are stable against fluctuating response delays. For this subset of stable attractors we observe sublinear scaling of the number of attractors with system size.Comment: extended version, additional figur

A stochastic and dynamical view of pluripotency in mouse embryonic stem cells

Pluripotent embryonic stem cells are of paramount importance for biomedical research thanks to their innate ability for self-renewal and differentiation into all major cell lines. The fateful decision to exit or remain in the pluripotent state is regulated by complex genetic regulatory network. Latest advances in transcriptomics have made it possible to infer basic topologies of pluripotency governing networks. The inferred network topologies, however, only encode boolean information while remaining silent about the roles of dynamics and molecular noise in gene expression. These features are widely considered essential for functional decision making. Herein we developed a framework for extending the boolean level networks into models accounting for individual genetic switches and promoter architecture which allows mechanistic interrogation of the roles of molecular noise, external signaling, and network topology. We demonstrate the pluripotent state of the network to be a broad attractor which is robust to variations of gene expression. Dynamics of exiting the pluripotent state, on the other hand, is significantly influenced by the molecular noise originating from genetic switching events which makes cells more responsive to extracellular signals. Lastly we show that steady state probability landscape can be significantly remodeled by global gene switching rates alone which can be taken as a proxy for how global epigenetic modifications exert control over stability of pluripotent states.Comment: 11 pages, 7 figure

Data-driven modelling of biological multi-scale processes

Biological processes involve a variety of spatial and temporal scales. A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales. In this manuscript we review mathematical modelling approaches used to describe the individual spatial scales and how they are integrated into holistic models. We discuss the relation between spatial and temporal scales and the implication of that on multi-scale modelling. Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes. In particular, we considered the availability of analysis tools for multi-scale models and model-based multi-scale data integration. We provide a compact review of methods for model-based data integration and model-based hypothesis testing. Furthermore, novel approaches and recent trends are discussed, including computation time reduction using reduced order and surrogate models, which contribute to the solution of inference problems. We conclude the manuscript by providing a few ideas for the development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and Multiscale Dynamics (American Scientific Publishers

Boolean Delay Equations: A simple way of looking at complex systems

Boolean Delay Equations (BDEs) are semi-discrete dynamical models with Boolean-valued variables that evolve in continuous time. Systems of BDEs can be classified into conservative or dissipative, in a manner that parallels the classification of ordinary or partial differential equations. Solutions to certain conservative BDEs exhibit growth of complexity in time. They represent therewith metaphors for biological evolution or human history. Dissipative BDEs are structurally stable and exhibit multiple equilibria and limit cycles, as well as more complex, fractal solution sets, such as Devil's staircases and ``fractal sunbursts``. All known solutions of dissipative BDEs have stationary variance. BDE systems of this type, both free and forced, have been used as highly idealized models of climate change on interannual, interdecadal and paleoclimatic time scales. BDEs are also being used as flexible, highly efficient models of colliding cascades in earthquake modeling and prediction, as well as in genetics. In this paper we review the theory of systems of BDEs and illustrate their applications to climatic and solid earth problems. The former have used small systems of BDEs, while the latter have used large networks of BDEs. We moreover introduce BDEs with an infinite number of variables distributed in space (``partial BDEs``) and discuss connections with other types of dynamical systems, including cellular automata and Boolean networks. This research-and-review paper concludes with a set of open questions.Comment: Latex, 67 pages with 15 eps figures. Revised version, in particular the discussion on partial BDEs is updated and enlarge

Topology of biological networks and reliability of information processing

Biological systems rely on robust internal information processing: Survival depends on highly reproducible dynamics of regulatory processes. Biological information processing elements, however, are intrinsically noisy (genetic switches, neurons, etc.). Such noise poses severe stability problems to system behavior as it tends to desynchronize system dynamics (e.g. via fluctuating response or transmission time of the elements). Synchronicity in parallel information processing is not readily sustained in the absence of a central clock. Here we analyze the influence of topology on synchronicity in networks of autonomous noisy elements. In numerical and analytical studies we find a clear distinction between non-reliable and reliable dynamical attractors, depending on the topology of the circuit. In the reliable cases, synchronicity is sustained, while in the unreliable scenario, fluctuating responses of single elements can gradually desynchronize the system, leading to non-reproducible behavior. We find that the fraction of reliable dynamical attractors strongly correlates with the underlying circuitry. Our model suggests that the observed motif structure of biological signaling networks is shaped by the biological requirement for reproducibility of attractors.Comment: 7 pages, 7 figure