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Stochastic gene

Seong Jun Park, Sanggeun Song, Gil-Suk Yang, Philip M Kim, Sangwoon Yoon, Ji-Hyun Kim, Jaeyoung Sung
Gene expression is a complex stochastic process composed of numerous enzymatic reactions with rates coupled to hidden cell-state variables. Despite advances in single-cell technologies, the lack of a theory accurately describing the gene expression process has restricted a robust, quantitative understanding of gene expression variability among cells. Here we present the Chemical Fluctuation Theorem (CFT), providing an accurate relationship between the environment-coupled chemical dynamics of gene expression and gene expression variability...
January 19, 2018: Nature Communications
Davit A Potoyan, Peter G Wolynes
The complex genetic programs of eukaryotic cells are often regulated by key transcription factors occupying or clearing out of a large number of genomic locations. Orchestrating the residence times of these factors is therefore important for the well organized functioning of a large network. The classic models of genetic switches sidestep this timing issue by assuming the binding of transcription factors to be governed entirely by thermodynamic protein-DNA affinities. Here we show that relying on passive thermodynamics and random release times can lead to a "time-scale crisis" for master genes that broadcast their signals to a large number of binding sites...
November 2017: Physical Review. E
Chen Jia, Michael Q Zhang, Hong Qian
Single-cell gene expression is inherently stochastic; its emergent behavior can be defined in terms of the chemical master equation describing the evolution of the mRNA and protein copy numbers as the latter tends to infinity. We establish two types of "macroscopic limits": the Kurtz limit is consistent with the classical chemical kinetics, while the Lévy limit provides a theoretical foundation for an empirical equation proposed in N. Friedman et al., Phys. Rev. Lett. 97, 168302 (2006)PRLTAO0031-900710.1103/PhysRevLett...
October 2017: Physical Review. E
Tameem Albash, Gene Wagenbreth, Itay Hen
We propose a Monte Carlo algorithm designed to simulate quantum as well as classical systems at equilibrium, bridging the algorithmic gap between quantum and classical thermal simulation algorithms. The method is based on a decomposition of the quantum partition function that can be viewed as a series expansion about its classical part. We argue that the algorithm not only provides a theoretical advancement in the field of quantum Monte Carlo simulations, but is optimally suited to tackle quantum many-body systems that exhibit a range of behaviors from "fully quantum" to "fully classical," in contrast to many existing methods...
December 2017: Physical Review. E
Chen Jia
Here we develop an effective approach to simplify two-time-scale Markov chains with infinite state spaces by removal of states with fast leaving rates, which improves the simplification method of finite Markov chains. We introduce the concept of fast transition paths and show that the effective transitions of the reduced chain can be represented as the superposition of the direct transitions and the indirect transitions via all the fast transition paths. Furthermore, we apply our simplification approach to the standard Markov model of single-cell stochastic gene expression and provide a mathematical theory of random gene expression bursts...
September 2017: Physical Review. E
Siwy Ling Yang, Guisheng Zeng, Fong Yee Chan, Yan-Ming Wang, Dongliang Yang, Yue Wang
Candida albicans cells homozygous at the mating-type locus stochastically undergo the white-to-opaque switching to become mating-competent. This switching is regulated by a core circuit of transcription factors organized through interlocking feedback loops around the master regulator Wor1. Although a range of distinct environmental cues is known to induce the switching, the pathways linking the external stimuli to the central control mechanism remains largely unknown. By screening a C. albicans haploid gene-deletion library, we found that SAC7 encoding a GTPase-activating protein of Rho1 is required for the white-to-opaque switching...
January 17, 2018: Scientific Reports
Zhipeng Wang, Davit A Potoyan, Peter G Wolynes
Gene regulatory networks must relay information from extracellular signals to downstream genes in an efficient, timely and coherent manner. Many complex functional tasks such as the immune response require system-wide broadcasting of information not to one but to many genes carrying out distinct functions whose dynamical binding and unbinding characteristics are widely distributed. In such broadcasting networks, the intended target sites are also often dwarfed in number by the even more numerous non-functional binding sites...
January 2018: Journal of the Royal Society, Interface
Chunhe Li
Landscape approaches have been exploited to study the stochastic dynamics of gene networks. However, how to calculate the landscape with a wide range of parameter variations and how to investigate the influence of the network topology on the global properties of gene networks remain to be elucidated. Here, I developed an approach for the landscape of random parameter perturbation (LRPP) to address this issue. Based on a self-consistent approximation approach, by making perturbations to parameters in a given range, I obtained the landscape for gene network systems...
January 17, 2018: Integrative Biology: Quantitative Biosciences From Nano to Macro
Yijin Ren, Can Wang, Zhi Chen, Elaine Allan, Henny C van der Mei, Henk J Busscher
Phenotypically-heterogeneous micro-environments emerge as biofilms mature across different environments. Phenotypic-heterogeneity in biofilm sub-populations not obeying quorum sensing-dictated, collective group-behavior, may be considered as a strategy allowing non-conformists to survive hostile conditions. Heterogeneous phenotype development has been amply studied with respect to gene expression and genotypic changes, but 'biofilm genes' responsible for pre-programmed development of heterogeneous micro-environments in biofilms have never been discovered...
January 9, 2018: FEMS Microbiology Reviews
Alessandro Bertucci, Junling Guo, Nicolas Oppmann, Agata Glab, Francesco Ricci, Frank Caruso, Francesca Cavalieri
Transcription factor DNA binding activity is of pivotal importance in living systems because of its primary involvement in the regulation of genetic machinery. The analysis of transient expression levels of transcription factors in response to a certain cell status is a powerful means for investigating cellular dynamics at the biomolecular level. Herein, a DNA-based molecular switch that enables probing of transcription factor DNA binding activity is directly used in living cells. We demonstrate that the DNA nanoswitch allows for dynamic fluorescence imaging of NF-κB and quantification of downstream gene silencing in real time...
January 11, 2018: Nanoscale
Anja Lück, Lukas Klimmasch, Peter Großmann, Sebastian Germerodt, Christoph Kaleta
Organisms need to adapt to changing environments and they do so by using a broad spectrum of strategies. These strategies include finding the right balance between expressing genes before or when they are needed, and adjusting the degree of noise inherent in gene expression. We investigated the interplay between different nutritional environments and the inhabiting organisms' metabolic and genetic adaptations by applying an evolutionary algorithm to an agent-based model of a concise bacterial metabolism. Our results show that constant environments and rapidly fluctuating environments produce similar adaptations in the organisms, making the predictability of the environment a major factor in determining optimal adaptation...
January 10, 2018: Scientific Reports
Roberto C Molina-Quiroz, Cecilia Silva-Valenzuela, Jennifer Brewster, Eduardo Castro-Nallar, Stuart B Levy, Andrew Camilli
Bacterial persistence is a transient, nonheritable physiological state that provides tolerance to bactericidal antibiotics. The stringent response, toxin-antitoxin modules, and stochastic processes, among other mechanisms, play roles in this phenomenon. How persistence is regulated is relatively ill defined. Here we show that cyclic AMP, a global regulator of carbon catabolism and other core processes, is a negative regulator of bacterial persistence in uropathogenic Escherichia coli, as measured by survival after exposure to a β-lactam antibiotic...
January 9, 2018: MBio
Martina M Yordanova, Gary Loughran, Alexander V Zhdanov, Marco Mariotti, Stephen J Kiniry, Patrick B F O'Connor, Dmitry E Andreev, Ioanna Tzani, Paul Saffert, Audrey M Michel, Vadim N Gladyshev, Dmitry B Papkovsky, John F Atkins, Pavel V Baranov
In addition to acting as template for protein synthesis, messenger RNA (mRNA) often contains sensory sequence elements that regulate this process. Here we report a new mechanism that limits the number of complete protein molecules that can be synthesized from a single mRNA molecule of the human AMD1 gene encoding adenosylmethionine decarboxylase 1 (AdoMetDC). A small proportion of ribosomes translating AMD1 mRNA stochastically read through the stop codon of the main coding region. These readthrough ribosomes then stall close to the next in-frame stop codon, eventually forming a ribosome queue, the length of which is proportional to the number of AdoMetDC molecules that were synthesized from the same AMD1 mRNA...
January 3, 2018: Nature
Maria Grazia Masiello, Roberto Verna, Alessandra Cucina, Mariano Bizzarri
Data obtained by studying mammalian cells in absence of gravity strongly support the notion that cell fate specification cannot be understood according to the current molecular model. A paradigmatic case in point is provided by studying cell populations growing in absence of gravity. When the physical constraint (gravity) is 'experimentally removed', cells spontaneously allocate into two morphologically different phenotypes. Such phenomenon is likely enacted by the intrinsic stochasticity, which, in turn, is successively 'canalized' by a specific gene regulatory network...
January 4, 2018: Progress in Biophysics and Molecular Biology
Enrico Ne, Robert-Jan Palstra, Tokameh Mahmoudi
In this review, we cover transcription regulation of human immunodeficiency virus type 1 (HIV-1) gene expression, focusing on the invaluable contributions, made by HIV research over the years, toward the field of transcription. In this context, the HIV promoter can be considered to be a well-studied model promoter, which although a viral promoter, is subject to the same cellular regulatory mechanisms that modulate the transcriptional control of endogenous host cellular genes. The molecular control of HIV-1 transcription has been well studied and considerable knowledge toward development of alternative strategies for therapies aimed at eradicating both active but also latent HIV-1 has been obtained...
2018: International Review of Cell and Molecular Biology
Rinat Arbel-Goren, Yonatan Shapira, Joel Stavans
A method is described for labeling individual messenger RNA (mRNA) transcripts in fixed bacteria for use in single-molecule fluorescence in situ hybridization (smFISH) experiments in E. coli. smFISH allows the measurement of cell-to-cell variability in mRNA copy number of genes of interest, as well as the subcellular location of the transcripts. The main steps involved are fixation of the bacterial cell culture, permeabilization of cell membranes, and hybridization of the target transcripts with sets of commercially available short fluorescently-labeled oligonucleotide probes...
December 21, 2017: Journal of Visualized Experiments: JoVE
Hui Liu, Peng Dong, Maria S Ioannou, Li Li, Jamien Shea, H Amalia Pasolli, Jonathan B Grimm, Patricia K Rivlin, Luke D Lavis, Minoru Koyama, Zhe Liu
Our ability to unambiguously image and track individual molecules in live cells is limited by packing of multiple copies of labeled molecules within the resolution limit. Here we devise a universal genetic strategy to precisely control copy number of fluorescently labeled molecules in a cell. This system has a dynamic range of ∼10,000-fold, enabling sparse labeling of proteins expressed at different abundance levels. Combined with photostable labels, this system extends the duration of automated single-molecule tracking by two orders of magnitude...
December 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
Jarosław Bryk, R Guy Reeves, Floyd A Reed, Jai A Denton
BACKGROUND: Synthetic systems that use positive feedback have been developed to control human disease vectors and crop pests. The tTAV system, which has been deployed in several insect species, relies on a positive feedback circuit that can be inhibited via dietary tetracycline. Although insects carrying tTAV fail to survive until adulthood in the absence of tetracycline, the exact reason for its lethality, as well as the transcriptomic effects of an active positive feedback circuit, remain unknown...
December 28, 2017: BMC Genomics
Andrew M Collins, Katherine J L Jackson
The immune systems of all mammals include populations of B cells producing antibodies with incredibly diverse specificities. Repertoire diversity has been described as the "miracle of immunology," and it was long thought to be the result of essentially stochastic processes. Recently, however, analysis of high throughput gene sequencing data has shown that hard-wired biases in these processes result in antibody repertoires that are broadly predictable. The repertoires of mice and humans are both predictable, but they are strikingly different...
December 19, 2017: Immunogenetics
Frits Veerman, Carsten Marr, Nikola Popović
The inherent stochasticity of gene expression in the context of regulatory networks profoundly influences the dynamics of the involved species. Mathematically speaking, the propagators which describe the evolution of such networks in time are typically defined as solutions of the corresponding chemical master equation (CME). However, it is not possible in general to obtain exact solutions to the CME in closed form, which is due largely to its high dimensionality. In the present article, we propose an analytical method for the efficient approximation of these propagators...
December 15, 2017: Journal of Mathematical Biology
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