Anna Terebus

State Space Truncation with Quantified Errors for Accurate Solutions to Discrete Chemical Master Equation

The discrete chemical master equation (dCME) provides a general framework for studying stochasticity in mesoscopic reaction networks. Since its direct solution rapidly becomes intractable due to the increasing size of the state space, truncation of the state space is necessary for solving most dCMEs. It is therefore important to assess the consequences of state space truncations so errors can be quantified and minimized. Here we describe a novel method for state space truncation. By partitioning a reaction network into multiple molecular equivalence groups (MEGs), we truncate the state space by limiting the total molecular copy numbers in each MEG. We further describe a theoretical framework for analysis of the truncation error in the steady-state probability landscape using reflecting boundaries. By aggregating the state space based on the usage of a MEG and constructing an aggregated Markov process, we show that the truncation error of a MEG can be asymptotically bounded by the probability of states on the reflecting boundary of the MEG. Furthermore, truncating states of an arbitrary MEG will not undermine the estimated error of truncating any other MEGs. We then provide an overall error estimate for networks with multiple MEGs. To rapidly determine the appropriate size of an arbitrary MEG, we also introduce an a priori method to estimate the upper bound of its truncation error. This a priori estimate can be rapidly computed from reaction rates of the network, without the need of costly trial solutions of the dCME. As examples, we show results of applying our methods to the four stochastic networks of (1) the birth and death model, (2) the single gene expression model, (3) the genetic toggle switch model, and (4) the phage lambda bistable epigenetic switch model. We demonstrate how truncation errors and steady-state probability landscapes can be computed using different sizes of the MEG(s) and how the results validate our theories. Overall, the novel state space truncation and error analysis methods developed here can be used to ensure accurate direct solutions to the dCME for a large number of stochastic networks.

Accurate Chemical Master Equation Solution Using Multi-Finite Buffers

The discrete chemical master equation (dCME) provides a fundamental framework for studying stochasticity in mesoscopic networks. Because of the multi-scale nature of many networks where reaction rates have large disparity, directly solving dCMEs is intractable due to the exploding size of the state space. It is important to truncate the state space effectively with quantified errors, so accurate solutions can be computed. It is also important to know if all major probabilistic peaks have been computed. Here we introduce the Accurate CME (ACME) algorithm for obtaining direct solutions to dCMEs. With multi-finite buffers for reducing the state space by O(n!), exact steady-state and time-evolving network probability landscapes can be computed. We further describe a theoretical framework of aggregating microstates into a smaller number of macrostates by decomposing a network into independent aggregated birth and death processes, and give an a priori method for rapidly determining steady-state truncation errors. The maximal sizes of the finite buffers for a given error tolerance can also be pre-computed without costly trial solutions of dCMEs. We show exactly computed probability landscapes of three multi-scale networks, namely, a 6-node toggle switch, 11-node phage-lambda epigenetic circuit, and 16-node MAPK cascade network, the latter two with no known solutions. We also show how probabilities of rare events can be computed from first-passage times, another class of unsolved problems challenging for simulation-based techniques due to large separations in time scales. Overall, the ACME method enables accurate and efficient solutions of the dCME for a large class of networks.

PRODIGEN: Visualizing the probability landscape of stochastic gene regulatory networks in state and time space

BackgroundVisualizing the complex probability landscape of stochastic gene regulatory networks can further biologists’ understanding of phenotypic behavior associated with specific genes.ResultsWe present PRODIGEN (PRObability DIstribution of GEne Networks), a web-based visual analysis tool for the systematic exploration of probability distributions over simulation time and state space in such networks. PRODIGEN was designed in collaboration with bioinformaticians who research stochastic gene networks. The analysis tool combines in a novel way existing, expanded, and new visual encodings to capture the time-varying characteristics of probability distributions: spaghetti plots over one dimensional projection, heatmaps of distributions over 2D projections, enhanced with overlaid time curves to display temporal changes, and novel individual glyphs of state information corresponding to particular peaks.ConclusionsWe demonstrate the effectiveness of the tool through two case studies on the computed probabilistic landscape of a gene regulatory network and of a toggle-switch network. Domain expert feedback indicates that our visual approach can help biologists: 1) visualize probabilities of stable states, 2) explore the temporal probability distributions, and 3) discover small peaks in the probability landscape that have potential relation to specific diseases.

Multiscale Modeling of Cellular Epigenetic States: Stochasticity in Molecular Networks, Chromatin Folding in Cell Nuclei, and Tissue Pattern Formation of Cells

Genome sequences provide the overall genetic blueprint of cells, but cells possessing the same genome can exhibit diverse phenotypes. There is a multitude of mechanisms controlling cellular epigenetic states and that dictate the behavior of cells. Among these, networks of interacting molecules, often under stochastic control, depending on the specific wirings of molecular components and the physiological conditions, can have a different landscape of cellular states. In addition, chromosome folding in three-dimensional space provides another important control mechanism for selective activation and repression of gene expression. Fully differentiated cells with different properties grow, divide, and interact through mechanical forces and communicate through signal transduction, resulting in the formation of complex tissue patterns. Developing quantitative models to study these multi-scale phenomena and to identify opportunities for improving human health requires development of theoretical models, algorithms, and computational tools. Here we review recent progress made in these important directions.

Exact computation of probability landscape of stochastic networks of Single Input and Coupled Toggle Switch Modules.

Gene regulatory networks depict the interactions between genes, proteins, and other components of the cell. These interactions often are stochastic that can influence behavior of the cells. Discrete Chemical Master Equation (dCME) provides a general framework for understanding the stochastic nature of these networks. However solving dCME is challenging due to the enormous state space, one effective approach is to study the behavior of individual modules of the stochastic network. Here we used the finite buffer dCME method and directly calculated the exact steady state probability landscape for the two stochastic networks of Single Input and Coupled Toggle Switch Modules. The first example is a switch network consisting of three genes, and the second example is a double switching network consisting of four coupled genes. Our results show complex switching behavior of these networks can be quantified.

Mechanisms of stochastic focusing and defocusing in biological reaction networks: Insight from accurate Chemical Master Equation (ACME) solutions

Stochasticity plays important roles in regulation of biochemical reaction networks when the copy numbers of molecular species are small. Studies based on Stochastic Simulation Algorithm (SSA) has shown that a basic reaction system can display stochastic focusing (SF) by increasing the sensitivity of the network as a result of the signal noise. Although SSA has been widely used to study stochastic networks, it is ineffective in examining rare events and this becomes a significant issue when the tails of probability distributions are relevant as is the case of SF. Here we use the ACME method to solve the exact solution of the discrete Chemical Master Equations and to study a network where SF was reported. We showed that the level of SF depends on the degree of the fluctuations of signal molecule. We discovered that signaling noise under certain conditions in the same reaction network can lead to a decrease in the system sensitivities, thus the network can experience stochastic defocusing. These results highlight the fundamental role of stochasticity in biological reaction networks and the need for exact computation of probability landscape of the molecules in the system.

Stochastic Focusing and Defocusing in Biological Reaction Networks: Lessons Learned from Accurate Chemical Master Equation (ACME) Solutions

Biological reaction networks are stochastic due to random thermal fluctuations. Stochasticity plays important roles in regulation of biochemical reaction networks when the copy numbers of molecular species are small and often results in unexpected outcomes. For example, it has been shown that a basic enzymatic reaction system can display stochastic focusing (SF) by increasing the sensitivity of the network as a result of the increasing signal noise [1]. Although stochastic simulation algorithm has been widely used to study such systems, it is ineffective in examining rare events and this becomes a significant issue when the tails of probability distributions are relevant as is the case of SF. Here we use the ACME method for the exact solution of the discrete Chemical Master Equation and study the probability landscape of product molecules in the basic enzymatic reaction system used in the original SF study [1]. Examinations of the effects of signal molecules under different stochastic processes show that SF is at play as stochastic changes enhance the system sensitivity. However, we also observed that the noise in signaling under certain stochastic processes in the same reaction network lead to a decrease in the system sensitivities, thus the network experiences stochastic defocusing. We further show that signal molecules following certain stochastic processes in the same reaction network can give rise to noise-induced bistability in the distribution of product molecules. These results highlight the fundamental role of stochasticity in biological reaction networks and the need for exact computation of probability landscape of the molecules in the system. It also points to possible importance of positive and negative feedback loops in such networks for control of the intrinsic noise.[1] Paulsson et. al, 2000, PNAS.