Characterization of noise in multistable genetic circuits reveals ways to modulate heterogeneity

Abstract

Random fluctuations in the amount of cellular components like mRNA and protein molecules are inevitable due to the stochastic and discrete nature of biochemical reactions. If large enough, this so-called “cellular noise” can lead to random transitions between the expression states of a multistable genetic circuit. That way, heterogeneity within isogenic populations is created. Our aim is to understand which dynamical features of a simple autoregulatory system determine its intrinsic noise level, and how they can be modified in order to regulate state-transitions. To that end, novel mathematical methods for the state-dependent characterization and prediction of noise in multistable systems are developed. First, we introduce the hybrid LNA, a modified version of the Linear Noise Approximation. It yields good predictions on variances of mRNA and protein fluctuations, even for reaction systems comprising low-copy-number components (e.g. mRNA) and highly nonlinear reaction rates. Furthermore, the temporal structure of fluctuations and the skewness of the protein distribution are characterized via state-dependent protein burst sizes and burst frequencies. Based on this mathematical framework, we develop graphical methods which support the intuitive design of regulatory circuits with a desired noise pattern. The methods are then used to predict how overall noise in the system can be adapted, and how state-specific noise modifications are possible that allow, e.g., the generation of unidirectional transitions. Our considerations are validated by stochastic simulations. This way, a design of genetic circuits is possible that takes population heterogeneity into account and is valuable in applications of synthetic biology and biotechnology. Moreover, natural phenomena like the bimodal development of genetic competence can be studied.

Theoretical study of the impact of adaptation on cell-fate heterogeneity and fractional killing

“…Diverse modelling approaches have proved useful to study stochastic switching in regulatory networks, ranging from the discrete chemical master equations and stochastic simulation algorithms to the continuous Fokker-Planck and Langevin equations. Those diverse tools and their refinements have been broadly used to study the interplay between noise properties and network topologies in shaping the steady-state bimodal distribution and transition rates associated with two phenotypic states 35 – 39 . In the present study, we use the joint framework of chemical Langevin equations 40 and bifurcation theory to address the interplay of stochasticity, transient adaptation and bistable switching.…”

Phenotypic noise and the cost of complexity

“…Phenotypic noise encompasses concepts such as developmental noise (Gavrilets and Hastings 1994), phenotypic hetero-geneity (Bódi et al 2017), cellular noise (Hortsch and Kremling 2018), biological noise (Eling et al 2019), intra-genotypic variability (Bruijning et al 2019), which take into account both intrinsic and extrinsic noises to varying degrees (Elowitz et al 2002). In quantitative genetics, phenotypic noise is historically known as environmental variance (or microenvironmental variability) (Falconer and Robertson 1956).…”

Fruit ripening in Lycium barbarum and Lycium ruthenicum is associated with distinct gene expression patterns

“…Another limitation of our study is high interindividual variability in gene expression levels (high SD values) observed for many samples. While a relatively high level of molecular noise is common in gene expression studies [86,87], high interindividual variability in gene expression was particularly pronounced in genes that are involved in environmental responses in Arabidopsis thaliana [88]. This is an indication that harsh environmental conditions may be causing pronouncedly volatile gene expression levels on the interindividual, or possibly even intraindividual, levels on relatively short time scales, but this hypothesis warrants further studies.…”