Phenotypic switching in gene regulatory networks Thomas, Philipp; Popović, Nikola; Grima, Ramon
Proceedings of the National Academy of Sciences - PNAS,
05/2014, Letnik:
111, Številka:
19
Journal Article
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Noise in gene expression can lead to reversible phenotypic switching. Several experimental studies have shown that the abundance distributions of proteins in a population of isogenic cells may ...display multiple distinct maxima. Each of these maxima may be associated with a subpopulation of a particular phenotype, the quantification of which is important for understanding cellular decision-making. Here, we devise a methodology which allows us to quantify multimodal gene expression distributions and single-cell power spectra in gene regulatory networks. Extending the commonly used linear noise approximation, we rigorously show that, in the limit of slow promoter dynamics, these distributions can be systematically approximated as a mixture of Gaussian components in a wide class of networks. The resulting closed-form approximation provides a practical tool for studying complex nonlinear gene regulatory networks that have thus far been amenable only to stochastic simulation. We demonstrate the applicability of our approach in a number of genetic networks, uncovering previously unidentified dynamical characteristics associated with phenotypic switching. Specifically, we elucidate how the interplay of transcriptional and translational regulation can be exploited to control the multimodality of gene expression distributions in two-promoter networks. We demonstrate how phenotypic switching leads to birhythmical expression in a genetic oscillator, and to hysteresis in phenotypic induction, thus highlighting the ability of regulatory networks to retain memory.
We study the three-timescale dynamics of a model that describes the El Niño Southern Oscillation (ENSO) phenomenon, which was proposed in Roberts et al. (2016). While ENSO phenomena are inherently ...characterised by the presence of multiple distinct timescales, the above model has previously been studied in a two-timescale context only. Here, we uncover the geometric mechanisms that are responsible for complex oscillatory dynamics in a three-timescale regime, and we demonstrate that the model exhibits a variety of qualitatively different behaviours in that regime, such as mixed-mode oscillation (MMO) with “plateaus” – trajectories where epochs of quiescence alternate with dramatic excursions – and relaxation oscillation. The latter, although emergent also in the two-timescale context in appropriate parameter regimes, had not been documented previously for this particular model. Moreover, we show that these mechanisms are relevant to models from other fields of ecological and population dynamics, as the underlying geometry is similar to the unfolding of Rosenzweig–MacArthur-type models in three dimensions.
•Studied geometrically a three-timescale model for the ENSO (El Niño Southern Oscillation) phenomenon.•Associated possible configurations of singular geometric objects to qualitatively different oscillatory dynamics.•Related delayed loss of stability in the model to the presence of a self-intersecting critical manifold.
The characterization of mechanisms involved in the positive effects of probiotic bacteria in various pathophysiological conditions is a prerogative for their safe and efficient application in ...biomedicine. We have investigated the immunological effects of live bacteria-free supernatant collected from GABA-producing Lactobacillus brevis BGZLS10-17 on Concanavalin A-stimulated mesenteric lymph node cells (MLNC), an in vitro model of activated immune cells. We have shown that GABA containing and GABA-free supernatant of Lactobacillus brevis BGZLS10-17 have strong immunoregulatory effects on MLNC. Further, GABA produced by this strain exhibit additional inhibitory effects on proliferation, IFN-γ and IL-17 production by MLNC, and the expression of MHCII and CD80 on antigen presenting cells. At the other hand, GABA-containing supernatants displayed the strongest stimulatory effects on the expression of immunoregulatory molecules, such as Foxp3
, IL-10, TGF-β, CTLA4 and SIRP-α. By looking for the mechanisms of actions, we found that supernatants produced by BGZLS10-17 induce autophagy in different MLNC, such as CD4
and CD8
T lymphocytes, NK and NKT cells, as well as antigen presenting cells. Further, we showed that the stimulation of Foxp3
, IL-10 and TGF-β expression by BGZLS10-17 produced GABA is completely mediated by the induction of ATG5 dependent autophagy, and that other molecules in the supernatants display GABA-, ATG5-, Foxp3
-, IL-10- and TGF-β- independent, immunoregulatory effects.
The host-microbiota cross-talk represents an important factor contributing to innate immune response and host resistance during infection. It has been shown that probiotic lactobacilli exhibit the ...ability to modulate innate immunity and enhance pathogen elimination. Here we showed that heat-inactivated probiotic strain Lactobacillus curvatus BGMK2-41 stimulates immune response and resistance of the Caenorhabditis elegans against Staphylococcus aureus and Pseudomonas aeruginosa. By employing qRT-PCR and western blot analysis we showed that heat-inactivated BGMK2-41 activated PMK-1/p38 MAPK immunity pathway which prolongs the survival of C. elegans exposed to pathogenic bacteria in nematode killing assays. The C. elegans pmk-1 mutant was used to demonstrate a mechanistic basis for the antimicrobial potential of BGMK2-41, showing that BGMK2-41 upregulated PMK-1/p38 MAPK dependent transcription of C-type lectins, lysozymes and tight junction protein CLC-1. Overall, this study suggests that PMK-1/p38 MAPK-dependent immune regulation by BGMK2-41 is essential for probiotic-mediated C. elegans protection against gram-positive and gram-negative bacteria and could be further explored for development of probiotics with the potential to increase resistance of the host towards pathogens.
Temporal variation of environmental stimuli leads to changes in gene expression. Since the latter is noisy and since many reaction events occur between the birth and death of an mRNA molecule, it is ...of interest to understand how a stimulus affects the transcript numbers measured at various sub-cellular locations. Here, we construct a stochastic model describing the dynamics of signal-dependent gene expression and its propagation downstream of transcription. For any time-dependent stimulus and assuming bursty gene expression, we devise a procedure which allows us to obtain time-dependent distributions of mRNA numbers at various stages of its life-cycle, e.g. in its nascent form at the transcription site, post-splicing in the nucleus, and after it is exported to the cytoplasm. We also derive an expression for the error in the approximation whose accuracy is verified via stochastic simulation. We find that, depending on the frequency of oscillation and the time of measurement, a stimulus can lead to cytoplasmic amplification or attenuation of transcriptional noise.
•We find closed-form mRNA distributions in response to time-dependent stimuli.•Our approach is based on a novel stochastic model reduction with quantifiable error.•Oscillations in the variance of mRNA fluctuations lag behind those in the mean.•The amplitude of the first two moments decreases monotonically with signal frequency.•The noise in mRNA fluctuations can increase or decrease with mRNA life-cycle stage.
Abstract
We study delayed loss of stability in a class of fast–slow systems with two fast variables and one slow one, where the linearisation of the fast vector field along a one-dimensional critical ...manifold has two real eigenvalues which intersect before the accumulated contraction and expansion are balanced along any individual eigendirection. That interplay between eigenvalues and eigendirections renders the use of known entry–exit relations unsuitable for calculating the point at which trajectories exit neighbourhoods of the given manifold. We illustrate the various qualitative scenarios that are possible in the class of systems considered here, and we propose novel formulae for the entry–exit functions that underlie the phenomenon of delayed loss of stability therein.
We consider a two-body problem with quick loss of mass which was formulated by Verhulst (Verhulst in J Inst Math Appl 18: 87–98, 1976). The corresponding dynamical system is singularly perturbed due ...to the presence of a small parameter in the governing equations which corresponds to the reciprocal of the initial rate of loss of mass, resulting in a boundary layer in the asymptotics. Here, we showcase a geometric approach which allows us to derive asymptotic expansions for the solutions of that problem via a combination of geometric singular perturbation theory (Fenichel in J Differ Equ 31: 53–98, 1979) and the desingularization technique known as “blow-up” (Dumortier, in: Bifurcations and Periodic Orbits of Vector Fields, Springer, Dordrecht, 1993). In particular, we justify the unexpected dependence of those expansions on fractional powers of the singular perturbation parameter; moreover, we show that the occurrence of logarithmic (“switchback”) terms therein is due to a resonance phenomenon that arises in one of the coordinate charts after blow-up.
Chronic lung diseases are a major and increasing global health problem, commonly caused by cigarette smoke. We aimed to explore the antioxidant effects of lactic acid bacteria (LAB) against cigarette ...smoke in bronchial epithelial cells.
The antioxidant effects of 21 heat-killed (HK) LAB strains were tested in cigarette smoke-stimulated BEAS-2B cells and 3-D bronchospheres organoids. We showed that HK Lactiplantibacillus plantarum BGPKM22 possesses antioxidant activity against cigarette smoke, resistance to hydrogen peroxide, and free radical neutralizing activity. We demonstrated that HK BGPKM22 inhibited cigarette smoke-induced expression of the Aryl hydrocarbon receptor (AhR) and Nuclear factor erythroid 2 related factor 2 (Nrf2) genes. The cell-free supernatant (SN) of BGPKM22 fully confirmed the effects of HK BGPKM22.
For the first time, we revealed that HK and SN of Lactip. plantarum BGPKM22 possess antioxidant activity and modulate AhR and Nrf2 gene expression in bronchial epithelial cells exposed to cigarette smoke.
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.
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