Stochastic Models Of Gene Expression Research Articles

Analysis of a detailed multi-stage model of stochastic gene expression using queueing theory and model reduction

We introduce a biologically detailed, stochastic model of gene expression describing the multiple rate-limiting steps of transcription, nuclear pre-mRNA processing, nuclear mRNA export, cytoplasmic mRNA degradation and translation of mRNA into protein. The processes in sub-cellular compartments are described by an arbitrary number of processing stages, thus accounting for a significantly finer molecular description of gene expression than conventional models such as the telegraph, two-stage and three-stage models of gene expression. We use two distinct tools, queueing theory and model reduction using the slow-scale linear-noise approximation, to derive exact or approximate analytic expressions for the moments or distributions of nuclear mRNA, cytoplasmic mRNA and protein fluctuations, as well as lower bounds for their Fano factors in steady-state conditions. We use these to study the phase diagram of the stochastic model; in particular we derive parametric conditions determining three types of transitions in the properties of mRNA fluctuations: from sub-Poissonian to super-Poissonian noise, from high noise in the nucleus to high noise in the cytoplasm, and from a monotonic increase to a monotonic decrease of the Fano factor with the number of processing stages. In contrast, protein fluctuations are always super-Poissonian and show weak dependence on the number of mRNA processing stages. Our results delineate the region of parameter space where conventional models give qualitatively incorrect results and provide insight into how the number of processing stages, e.g. the number of rate-limiting steps in initiation, splicing and mRNA degradation, shape stochastic gene expression by modulation of molecular memory.

Exact solution of a three-stage model of stochastic gene expression including cell-cycle dynamics

The classical three-stage model of stochastic gene expression predicts the statistics of single cell mRNA and protein number fluctuations as a function of the rates of promoter switching, transcription, translation, degradation and dilution. While this model is easily simulated, its analytical solution remains an unsolved problem. Here we modify this model to explicitly include cell-cycle dynamics and then derive an exact solution for the time-dependent joint distribution of mRNA and protein numbers. We show large differences between this model and the classical model which captures cell-cycle effects implicitly via effective first-order dilution reactions. In particular we find that the Fano factor of protein numbers calculated from a population snapshot measurement are underestimated by the classical model whereas the correlation between mRNA and protein can be either over- or underestimated, depending on the timescales of mRNA degradation and promoter switching relative to the mean cell-cycle duration time.

The asymptotic tails of limit distributions of continuous-time Markov chains

Abstract This paper investigates tail asymptotics of stationary distributions and quasi-stationary distributions (QSDs) of continuous-time Markov chains on subsets of the non-negative integers. Based on the so-called flux-balance equation, we establish identities for stationary measures and QSDs, which we use to derive tail asymptotics. In particular, for continuous-time Markov chains with asymptotic power law transition rates, tail asymptotics for stationary distributions and QSDs are classified into three types using three easily computable parameters: (i) super-exponential distributions, (ii) exponential-tailed distributions, and (iii) sub-exponential distributions. Our approach to establish tail asymptotics of stationary distributions is different from the classical semimartingale approach, and we do not impose ergodicity or moment bound conditions. In particular, the results also hold for explosive Markov chains, for which multiple stationary distributions may exist. Furthermore, our results on tail asymptotics of QSDs seem new. We apply our results to biochemical reaction networks, a general single-cell stochastic gene expression model, an extended class of branching processes, and stochastic population processes with bursty reproduction, none of which are birth–death processes. Our approach, together with the identities, easily extends to discrete-time Markov chains.

Uncovering the effect of RNA polymerase steric interactions on gene expression noise: Analytical distributions of nascent and mature RNA numbers.

The telegraph model is the standard model of stochastic gene expression, which can be solved exactly to obtain the distribution of mature RNA numbers per cell. A modification of this model also leads to an analytical distribution of nascent RNA numbers. These solutions are routinely used for the analysis of single-cell data, including the inference of transcriptional parameters. However, these models neglect important mechanistic features of transcription elongation, such as the stochastic movement of RNA polymerases and their steric (excluded-volume) interactions. Here we construct a model of gene expression describing promoter switching between inactive and active states, binding of RNA polymerases in the active state, their stochastic movement including steric interactions along the gene, and their unbinding leading to a mature transcript that subsequently decays. We derive the steady-state distributions of the nascent and mature RNA numbers in two important limiting cases: constitutive expression and slow promoter switching. We show that RNA fluctuations are suppressed by steric interactions between RNA polymerases, and that this suppression can in some instances even lead to sub-Poissonian fluctuations; these effects are most pronounced for nascent RNA and less prominent for mature RNA, since the latter is not a direct sensor of transcription. We find a relationship between the parameters of our microscopic mechanistic model and those of the standard models that ensures excellent consistency in their prediction of the first and second RNA number moments over vast regions of parameter space, encompassing slow, intermediate, and rapid promoter switching, provided the RNA number distributions are Poissonian or super-Poissonian. Furthermore, we identify the limitations of inference from mature RNA data, specifically showing that it cannot differentiate between highly distinct RNA polymerase traffic patterns on a gene.

Out-of-equilibrium gene expression fluctuations in the presence of extrinsic noise

Cell-to-cell variability in protein concentrations is strongly affected by extrinsic noise, especially for highly expressed genes. Extrinsic noise can be due to fluctuations of several possible cellular factors connected to cell physiology and to the level of key enzymes in the expression process. However, how to identify the predominant sources of extrinsic noise in a biological system is still an open question. This work considers a general stochastic model of gene expression with extrinsic noise represented as fluctuations of the different model rates, and focuses on the out-of-equilibrium expression dynamics. Combining analytical calculations with stochastic simulations, we characterize how extrinsic noise shapes the protein variability during gene activation or inactivation, depending on the prevailing source of extrinsic variability, on its intensity and timescale. In particular, we show that qualitatively different noise profiles can be identified depending on which are the fluctuating parameters. This indicates an experimentally accessible way to pinpoint the dominant sources of extrinsic noise using time-coarse experiments.

Bayesian filtering for model predictive control of stochastic gene expression in single cells

This study describes a method for controlling the production of protein in individual cells using stochastic models of gene expression. By combining modern microscopy platforms with optogenetic gene expression, experimentalists are able to accurately apply light to individual cells, which can induce protein production. Here we use a finite state projection based stochastic model of gene expression, along with Bayesian state estimation to control protein copy numbers within individual cells. We compare this method to previous methods that use population based approaches. We also demonstrate the ability of this control strategy to ameliorate discrepancies between the predictions of a deterministic model and stochastic switching system.

A Markovian arrival stream approach to stochastic gene expression in cells.

We analyse a generalisation of the stochastic gene expression model studied recently in Fromion et al. (SIAM J Appl Math 73:195-211, 2013) and Robert (Probab Surv 16:277-332, 2019) that keeps track of the production of both mRNA and protein molecules, using techniques from the theory of point processes, as well as ideas from the theory of matrix-analytic methods. Here, both the activity of a gene and the creation of mRNA are modelled with an arbitrary Markovian Arrival Process governed by finitely many phases, and each mRNA molecule during its lifetime gives rise to protein molecules in accordance with a Poisson process. This modification is important, as Markovian Arrival Processes can be used to approximate many types of point processes on the nonnegative real line, meaning this framework allows us to further relax our assumptions on the overall process of transcription.

Probability landscape of a stochastic model of gene expression in single cells through exact solution of chemical master equation

Gene expression is a fundamental process enabling different cellular functions. However, genetically identical cells under the same environmental conditions exhibit large variability in gene expression. Such stochasticity has been shown to play central roles in determining cellular processes. In this study, we provide full characterizations of the stochastic effect of a model of gene transcription. Specifically, we model the transcription process using the simplified two-state reaction network. By examining the effects of different reaction rates, we computed exact steady-state probability landscapes at different combinations of reaction rates using the finite-buffer Accurate Chemical Master Equation (ACME) algorithm.

The effect of microRNA on protein variability and gene expression fidelity

Small regulatory RNA molecules such as microRNA modulate gene expression through inhibiting the translation of messenger RNA (mRNA). Such post-transcriptional regulation has been recently hypothesized to reduce the stochastic variability of gene expression around average levels. Here we quantify noise in stochastic gene expression models with and without such regulation. Our results suggest that silencing mRNA post-transcriptionally will always increase rather than decrease gene expression noise when the silencing of mRNA also increases its degradation as is expected for microRNA interactions with mRNA. In that regime we also find that silencing mRNA generally reduces the fidelity of signal transmission from deterministically varying upstream factors to protein levels. These findings suggest that microRNA binding to mRNA does not generically confer precision to protein expression.

The effect of microRNA on protein variability and gene expression fidelity

Small regulatory RNA molecules such as microRNA modulate gene expression through inhibiting the translation of messenger RNA (mRNA). Such posttranscriptional regulation has been recently hypothesized to reduce the stochastic variability of gene expression around average levels. Here, we quantify noise in stochastic gene expression models with and without such regulation. Our results suggest that silencing mRNA posttranscriptionally will always increase, rather than decrease, gene expression noise when the silencing of mRNA also increases its degradation, as is expected for microRNA interactions with mRNA. In that regime, we also find that silencing mRNA generally reduces the fidelity of signal transmission from deterministically varying upstream factors to protein levels. These findings suggest that microRNA binding to mRNA does not generically confer precision to protein expression.

Stationarity and Inference in Multistate Promoter Models of Stochastic Gene Expression via Stick-Breaking Measures

Stationarity and Inference in Multistate Promoter Models of Stochastic Gene Expression via Stick-Breaking Measures

Concentration fluctuations in growing and dividing cells: Insights into the emergence of concentration homeostasis.

Intracellular reaction rates depend on concentrations and hence their levels are often regulated. However classical models of stochastic gene expression lack a cell size description and cannot be used to predict noise in concentrations. Here, we construct a model of gene product dynamics that includes a description of cell growth, cell division, size-dependent gene expression, gene dosage compensation, and size control mechanisms that can vary with the cell cycle phase. We obtain expressions for the approximate distributions and power spectra of concentration fluctuations which lead to insight into the emergence of concentration homeostasis. We find that (i) the conditions necessary to suppress cell division-induced concentration oscillations are difficult to achieve; (ii) mRNA concentration and number distributions can have different number of modes; (iii) two-layer size control strategies such as sizer-timer or adder-timer are ideal because they maintain constant mean concentrations whilst minimising concentration noise; (iv) accurate concentration homeostasis requires a fine tuning of dosage compensation, replication timing, and size-dependent gene expression; (v) deviations from perfect concentration homeostasis show up as deviations of the concentration distribution from a gamma distribution. Some of these predictions are confirmed using data for E. coli, fission yeast, and budding yeast.

Full classification of dynamics for one-dimensional continuous-time Markov chains with polynomial transition rates

AbstractThis paper provides a full classification of the dynamics for continuous-time Markov chains (CTMCs) on the nonnegative integers with polynomial transition rate functions and without arbitrary large backward jumps. Such stochastic processes are abundant in applications, in particular in biology. More precisely, for CTMCs of bounded jumps, we provide necessary and sufficient conditions in terms of calculable parameters for explosivity, recurrence versus transience, positive recurrence versus null recurrence, certain absorption, and implosivity. Simple sufficient conditions for exponential ergodicity of stationary distributions and quasi-stationary distributions as well as existence and nonexistence of moments of hitting times are also obtained. Similar simple sufficient conditions for the aforementioned dynamics together with their opposite dynamics are established for CTMCs with unbounded forward jumps. Finally, we apply our results to stochastic reaction networks, an extended class of branching processes, a general bursty single-cell stochastic gene expression model, and population processes, none of which are birth–death processes. The approach is based on a mixture of Lyapunov–Foster-type results, the classical semimartingale approach, and estimates of stationary measures.

Inference and uncertainty quantification of stochastic gene expression via synthetic models.

Estimating uncertainty in model predictions is a central task in quantitative biology. Biological models at the single-cell level are intrinsically stochastic and nonlinear, creating formidable challenges for their statistical estimation which inevitably has to rely on approximations that trade accuracy for tractability. Despite intensive interest, a sweet spot in this trade-off has not been found yet. We propose a flexible procedure for uncertainty quantification in a wide class of reaction networks describing stochastic gene expression including those with feedback. The method is based on creating a tractable coarse-graining of the model that is learned from simulations, a synthetic model, to approximate the likelihood function. We demonstrate that synthetic models can substantially outperform state-of-the-art approaches on a number of non-trivial systems and datasets, yielding an accurate and computationally viable solution to uncertainty quantification in stochastic models of gene expression.

Emergent expression of fitness-conferring genes by phenotypic selection.

Genotypic and phenotypic adaptation is the consequence of ongoing natural selection in populations and is key to predicting and preventing drug resistance. Whereas classic antibiotic persistence is all-or-nothing, here we demonstrate that an antibiotic resistance gene displays linear dose-responsive selection for increased expression in proportion to rising antibiotic concentration in growing Escherichia coli populations. Furthermore, we report the potentially wide-spread nature of this form of emergent gene expression (EGE) by instantaneous phenotypic selection process under bactericidal and bacteriostatic antibiotic treatment, as well as an amino acid synthesis pathway enzyme under a range of auxotrophic conditions. We propose an analogy to Ohm's law in electricity (V = IR), where selection pressure acts similarly to voltage (V), gene expression to current (I), and resistance (R) to cellular machinery constraints and costs. Lastly, mathematical modeling using agent-based models of stochastic gene expression in growing populations and Bayesian model selection reveal that the EGE mechanism requires variability in gene expression within an isogenic population, and a cellular "memory" from positive feedbacks between growth and expression of any fitness-conferring gene. Finally, we discuss the connection of the observed phenomenon to a previously described general fluctuation-response relationship in biology.

Exact distributions for stochastic gene expression models with arbitrary promoter architecture and translational bursting.

Gene expression in individual cells is inherently variable and sporadic, leading to cell-to-cell variability in mRNA and protein levels. Recent single-cell and single-molecule experiments indicate that promoter architecture and translational bursting play significant roles in controlling gene expression noise and generating the phenotypic diversity that life exhibits. To quantitatively understand the impact of these factors, it is essential to construct an accurate mathematical description of stochastic gene expression and find the exact analytical results, which is a formidable task. Here, we develop a stochastic model of bursty gene expression, which considers the complex promoter architecture governing the variability in mRNA expression and a general distribution characterizing translational burst. We derive the analytical expression for the corresponding protein steady-state distribution and all moment statistics of protein counts. We show that the total protein noise can be decomposed into three parts: the low-copy noise of protein due to probabilistic individual birth and death events, the noise due to stochastic switching between promoter states, and the noise resulting from translational busting. The theoretical results derived provide quantitative insights into the biochemical mechanisms of stochastic gene expression.

Reduction of a stochastic model of gene expression: Lagrangian dynamics gives access to basins of attraction as cell types and metastabilty.

Differentiation is the process whereby a cell acquires a specific phenotype, by differential gene expression as a function of time. This is thought to result from the dynamical functioning of an underlying Gene Regulatory Network (GRN). The precise path from the stochastic GRN behavior to the resulting cell state is still an open question. In this work we propose to reduce a stochastic model of gene expression, where a cell is represented by a vector in a continuous space of gene expression, to a discrete coarse-grained model on a limited number of cell types. We develop analytical results and numerical tools to perform this reduction for a specific model characterizing the evolution of a cell by a system of piecewise deterministic Markov processes (PDMP). Solving a spectral problem, we find the explicit variational form of the rate function associated to a large deviations principle, for any number of genes. The resulting Lagrangian dynamics allows us to define a deterministic limit of which the basins of attraction can be identified to cellular types. In this context the quasipotential, describing the transitions between these basins in the weak noise limit, can be defined as the unique solution of an Hamilton-Jacobi equation under a particular constraint. We develop a numerical method for approximating the coarse-grained model parameters, and show its accuracy for a symmetric toggle-switch network. We deduce from the reduced model an approximation of the stationary distribution of the PDMP system, which appears as a Beta mixture. Altogether those results establish a rigorous frame for connecting GRN behavior to the resulting cellular behavior, including the calculation of the probability of jumps between cell types.

Exploring dissipative sources of non-Markovian biochemical reaction systems.

Many biological processes including important intracellular processes are governed by biochemical reaction networks. Usually, these reaction systems operate far from thermodynamic equilibrium, implying free-energy dissipation. On the other hand, single reaction events happen often in a memory manner, leading to non-Markovian kinetics. A question then arises: how do we calculate free-energy dissipation (defined as the entropy production rate) in this physically real case? We derive an analytical formula for calculating the energy consumption of a general reaction system with molecular memory characterized by nonexponential waiting-time distributions. It shows that this dissipation is composed of two parts: one from broken detailed balance of an equivalent Markovian system with the same topology and substrates, and the other from the direction-time dependence of waiting-time distributions. But, if the system is in a detailed balance and the waiting-time distribution is direction-time independent, there is no energy dissipation even in the non-Markovian case. These general results provide insights into the physical mechanisms underlying nonequilibrium processes. A continuous-time random-walk model and a generalized model of stochastic gene expression are chosen to clearly show dissipative sources and the relationship between energy dissipation and molecular memory.

Parameter inference with analytical propagators for stochastic models of autoregulated gene expression

Abstract Stochastic gene expression in regulatory networks is conventionally modelled via the chemical master equation (CME). As explicit solutions to the CME, in the form of so-called propagators, are oftentimes not readily available, various approximations have been proposed. A recently developed analytical method is based on a separation of time scales that assumes significant differences in the lifetimes of mRNA and protein in the network, allowing for the efficient approximation of propagators from asymptotic expansions for the corresponding generating functions. Here, we showcase the applicability of that method to simulated data from a ‘telegraph’ model for gene expression that is extended with an autoregulatory mechanism. We demonstrate that the resulting approximate propagators can be applied successfully for parameter inference in the non-regulated model; moreover, we show that, in the extended autoregulated model, autoactivation or autorepression may be refuted under certain assumptions on the model parameters. These results indicate that our approach may allow for successful parameter inference and model identification from longitudinal single cell data.

Identification of stochastic gene expression models over lineage trees

In previous work, we have developed an autoregressive Mixed-Effects model of the evolution of the kinetic gene expression parameters along cell generations, and an identification method simultaneously exploiting single-cell gene expression profiles and known parental relationships among cells (lineage tree data). Here, we extend our modelling and identification approach to explicitly account for stochasticity of promoter activation, and demonstrate via simulation the performance of the method and the improvement relative to the original approach where this source of noise is not accounted for.