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Abstract In the last decade, the interactions among histone modifications and DNA methylation and their effect on the DNA structure, i.e., chromatin state, have been identified as key mediators for the maintenance of cell identity, defined as epigenetic cell memory. In this paper, we determine how the positive feedback loops generated by the auto and crosscatalysis among repressive modifications affect the temporal duration of the cell identity. To this end, we conduct a stochastic analysis of a recently published chromatin modification circuit considering two limiting behaviors: fast erasure rate of repressive histone modifications or fast erasure rate of DNA methylation. In order to perform this mathematical analysis, we first show that the deterministic model of the system is a singular singularly perturbed (SSP) system and use a model reduction approach for SSP systems to obtain a reduced onedimensional model. We thus analytically evaluate the reduced system’s stationary probability distribution and the mean switching time between active and repressed chromatin states. We then add a computational study of the original reaction model to validate and extend the analytical findings. Our results show that the absence of DNA methylation reduces the bias of the system’s stationary probability distribution toward the repressed chromatin state and the temporal duration of this state’s memory. In the absence of repressive histone modifications, we also observe that the time needed to reactivate a repressed gene with an activating input is less stochastic, suggesting that repressive histone modifications specifically contribute to the highly variable latency of state reactivation.more » « less

Abstract Continuoustime Markov chains are frequently used as stochastic models for chemical reaction networks, especially in the growing field of systems biology. A fundamental problem for these Stochastic Chemical Reaction Networks (SCRNs) is to understand the dependence of the stochastic behavior of these systems on the chemical reaction rate parameters. Towards solving this problem, in this paper we develop theoretical tools called comparison theorems that provide stochastic ordering results for SCRNs. These theorems give sufficient conditions for monotonic dependence on parameters in these network models, which allow us to obtain, under suitable conditions, information about transient and steadystate behavior. These theorems exploit structural properties of SCRNs, beyond those of general continuoustime Markov chains. Furthermore, we derive two theorems to compare stationary distributions and mean first passage times for SCRNs with different parameter values, or with the same parameters and different initial conditions. These tools are developed for SCRNs taking values in a generic (finite or countably infinite) state space and can also be applied for nonmassaction kinetics models. When propensity functions are bounded, our method of proof gives an explicit method for coupling two comparable SCRNs, which can be used to simultaneously simulate their sample paths in a comparable manner. We illustrate our results with applications to models of enzymatic kinetics and epigenetic regulation by chromatin modifications.

Epigenetic cell memory (ECM), the inheritance of gene expression patterns without changes in genetic sequence, is a critical property of multicellular organisms. Chromatin state, as dictated by histone covalent modifications, has recently appeared as a mediator of ECM. In this paper, we conduct a stochastic analysis of the histone modification circuit that controls chromatin state to determine key biological parameters that affect ECM. Specifically, we derive a onedimensional Markov chain model of the circuit and analytically evaluate both the stationary probability distribution of chromatin state and the mean time to switch between active and repressed chromatin states. We then validate our analytical findings using stochastic simulations of the original higher dimensional circuit reaction model. Our analysis shows that as the speed of basal decay of histone modifications decreases compared to the speed of autocatalysis, the stationary probability distribution becomes bimodal and increasingly concentrated about the active and repressed chromatin states. Accordingly, the switching time between active and repressed chromatin states becomes larger. These results indicate that time scale separation among key constituent processes of the histone modification circuit controls ECM.more » « less

Herrmann, Carl (Ed.)Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that longterm persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from timescale separation among three circuit’s constituent processes: basal erasure, auto and crosscatalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as timescale separation increases, but more so for the repressed state. This asymmetry stems from the crosscatalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TFmediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, longterm distinct gene expression patterns arise, which are also robust to failure in the regulatory links.more » « less

null (Ed.)Abstract Unlimited access to a motorway network can, in overloaded conditions, cause a loss of throughput. Ramp metering, by controlling access to the motorway at onramps, can help avoid this loss of throughput. The queues that form at onramps are dependent on the metering rates chosen at the onramps, and these choices affect how the capacities of different motorway sections are shared amongst competing flows. In this paper we perform an analytical study of a fluid, or differential equation, model of a linear network topology with onramp queues. The model allows for adaptive arrivals, in the sense that the rate at which external traffic enters the queue at an onramp can depend on the current perceived delay in that queue. The model also includes a ramp metering policy which uses global onramp queue length information to determine the rate at which traffic enters the motorway from each onramp. This ramp metering policy minimizes the maximum delay over all onramps and produces equal delay times over many onramps. The paper characterizes both the dynamics and the equilibrium behavior of the system under this policy. While we consider an idealized model that leaves out many practical details, an aim of the paper is to develop analytical methods that yield interesting qualitative insights and might be adapted to more general contexts. The paper can be considered as a step in developing an analytical approach towards studying more complex network topologies and incorporating other model features.more » « less

null (Ed.)This work concerns the asymptotic behavior of solutions to a (strictly) subcritical fluid model for a data communication network, where file sizes are generally distributed and the network operates under a fair bandwidthsharing policy. Here we consider fair bandwidthsharing policies that are a slight generalization of the [Formula: see text]fair policies introduced by Mo and Walrand [Mo J, Walrand J (2000) Fair endtoend windowbased congestion control. IEEE/ACM Trans. Networks 8(5):556–567.]. Since the year 2000, it has been a standing problem to prove stability of the data communications network model of Massoulié and Roberts [Massoulié L, Roberts J (2000) Bandwidth sharing and admission control for elastic traffic. Telecommunication Systems 15(1):185–201.], with general file sizes and operating under fair bandwidth sharing policies, when the offered load is less than capacity (subcritical conditions). A crucial step in an approach to this problem is to prove stability of subcritical fluid model solutions. In 2012, Paganini et al. [Paganini F, Tang A, Ferragut A, Andrew LLH (2012) Network stability under alpha fair bandwidth allocation with general file size distribution. IEEE Trans. Automatic Control 57(3):579–591.] introduced a Lyapunov function for this purpose and gave an argument, assuming that fluid model solutions are sufficiently smooth in time and space that they are strong solutions of a partial differential equation and assuming that no fluid level on any route touches zero before all route levels reach zero. The aim of the current paper is to prove stability of the subcritical fluid model without these strong assumptions. Starting with a slight generalization of the Lyapunov function proposed by Paganini et al., assuming that each component of the initial state of a measurevalued fluid model solution, as well as the file size distributions, have no atoms and have finite first moments, we prove absolute continuity in time of the composition of the Lyapunov function with any subcritical fluid model solution and describe the associated density. We use this to prove that the Lyapunov function composed with such a subcritical fluid model solution converges to zero as time goes to infinity. This implies that each component of the measurevalued fluid model solution converges vaguely on [Formula: see text] to the zero measure as time goes to infinity. Under the further assumption that the file size distributions have finite pth moments for some p > 1 and that each component of the initial state of the fluid model solution has finite pth moment, it is proved that the fluid model solution reaches the measure with all components equal to the zero measure in finite time and that the time to reach this zero state has a uniform bound for all fluid model solutions having a uniform bound on the initial total mass and the pth moment of each component of the initial state. In contrast to the analysis of Paganini et al., we do not need their strong smoothness assumptions on fluid model solutions and we rigorously treat the realistic, but singular situation, where the fluid level on some routes becomes zero, whereas other route levels remain positive.more » « less