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Stochastic gene

Ruben Perez-Carrasco, Pilar Guerrero, James Briscoe, Karen M Page
During tissue development, patterns of gene expression determine the spatial arrangement of cell types. In many cases, gradients of secreted signalling molecules-morphogens-guide this process by controlling downstream transcriptional networks. A mechanism commonly used in these networks to convert the continuous information provided by the gradient into discrete transitions between adjacent cell types is the genetic toggle switch, composed of cross-repressing transcriptional determinants. Previous analyses have emphasised the steady state output of these mechanisms...
October 2016: PLoS Computational Biology
Nikolaos Tsamandouras, Tomasz Kostrzewski, Cynthia L Stokes, Linda G Griffith, David J Hughes, Murat Cirit
In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from 5 different donors cultured in a perfused 3D human liver microphysiological system and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of 6 compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability (LDH release, albumin and urea production)...
October 19, 2016: Journal of Pharmacology and Experimental Therapeutics
Ornella Affinito, Giovanni Scala, Domenico Palumbo, Ermanno Florio, Antonella Monticelli, Gennaro Miele, Vittorio Enrico Avvedimento, Alessandro Usiello, Lorenzo Chiariotti, Sergio Cocozza
DNA methylation is often analyzed by reporting the average methylation degree of each cytosine. In this study, we used a single molecule methylation analysis in order to look at the methylation conformation of individual molecules. Using D-aspartate oxidase as a model gene, we performed an in-depth methylation analysis through the developmental stages of three different mouse tissues (brain, lung, and gut), where this gene undergoes opposite methylation destiny. This approach allowed us to track both methylation and demethylation processes at high resolution...
October 17, 2016: Epigenetics: Official Journal of the DNA Methylation Society
Alireza Karbalayghareh, Ulisses Braga-Neto, Jianping Hua, Edward R Dougherty
Gene-expression-based phenotype classification is used for disease diagnosis and prognosis relating to treatment strategies. The present paper considers classification based on sequential measurements of multiple genes using gene regulatory network (GRN) modeling. There are two networks, original and mutated, and observations consist of trajectories of network states. The problem is to classify an observation trajectory as coming from either the original or mutated network. GRNs are modeled via probabilistic Boolean networks, which incorporate stochasticity at both the gene and network levels...
October 11, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Jakub Jędrak, Anna Ochab-Marcinek
We study a stochastic model of gene expression, in which protein production has a form of random bursts whose size distribution is arbitrary, whereas protein decay is a first-order reaction. We find exact analytical expressions for the time evolution of the cumulant-generating function for the most general case when both the burst size probability distribution and the model parameters depend on time in an arbitrary (e.g., oscillatory) manner, and for arbitrary initial conditions. We show that in the case of periodic external activation and constant protein degradation rate, the response of the gene is analogous to the resistor-capacitor low-pass filter, where slow oscillations of the external driving have a greater effect on gene expression than the fast ones...
September 2016: Physical Review. E
Laurent Potvin-Trottier, Nathan D Lord, Glenn Vinnicombe, Johan Paulsson
Synthetically engineered genetic circuits can perform a wide variety of tasks but are generally less accurate than natural systems. Here we revisit the first synthetic genetic oscillator, the repressilator, and modify it using principles from stochastic chemistry in single cells. Specifically, we sought to reduce error propagation and information losses, not by adding control loops, but by simply removing existing features. We show that this modification created highly regular and robust oscillations. Furthermore, some streamlined circuits kept 14 generation periods over a range of growth conditions and kept phase for hundreds of generations in single cells, allowing cells in flasks and colonies to oscillate synchronously without any coupling between them...
October 12, 2016: Nature
Pablo Villegas, José Ruiz-Franco, Jorge Hidalgo, Miguel A Muñoz
Gene regulatory networks can be successfully modeled as Boolean networks. A much discussed hypothesis says that such model networks reproduce empirical findings the best if they are tuned to operate at criticality, i.e. at the borderline between their ordered and disordered phases. Critical networks have been argued to lead to a number of functional advantages such as maximal dynamical range, maximal sensitivity to environmental changes, as well as to an excellent tradeoff between stability and flexibility...
October 7, 2016: Scientific Reports
Matthew Z Anderson, Allison M Porman, Na Wang, Eugenio Mancera, Denis Huang, Christina A Cuomo, Richard J Bennett
Heritable epigenetic changes underlie the ability of cells to differentiate into distinct cell types. Here, we demonstrate that the fungal pathogen Candida tropicalis exhibits multipotency, undergoing stochastic and reversible switching between three cellular states. The three cell states exhibit unique cellular morphologies, growth rates, and global gene expression profiles. Genetic analysis identified six transcription factors that play key roles in regulating cell differentiation. In particular, we show that forced expression of Wor1 or Efg1 transcription factors can be used to manipulate transitions between all three cell states...
October 2016: PLoS Genetics
Weilin Peng, Ruijie Song, Murat Acar
Genetic noise together with genome duplication and volume changes during cell cycle are significant contributors to cell-to-cell heterogeneity. How can cells buffer the effects of these unavoidable epigenetic and genetic variations on phenotypes that are sensitive to such variations? Here we show that a simple network motif that is essential for network-dosage compensation can reduce the effects of extrinsic noise on the network output. Using natural and synthetic gene networks with and without the network motif, we measure gene network activity in single yeast cells and find that the activity of the compensated network is significantly lower in noise compared with the non-compensated network...
October 3, 2016: Nature Communications
Silvia Urbansky, Paula González Avalos, Maike Wosch, Steffen Lemke
Gastrulation constitutes a fundamental yet diverse morphogenetic process of metazoan development. Modes of gastrulation range from stochastic translocation of individual cells to coordinated infolding of an epithelial sheet. How such morphogenetic differences are genetically encoded and whether they have provided specific developmental advantages is unclear. Here we identify two genes, folded gastrulation and t48, which in the evolution of fly gastrulation acted as a likely switch from an ingression of individual cells to the invagination of the blastoderm epithelium...
September 29, 2016: ELife
Kenn Gerdes
Bacteria form persisters, cells that are tolerant to multiple antibiotics and other types of environmental stress. Persister formation can be induced either stochastically in single cells of a growing bacterial ensemble, or by environmental stresses, such as nutrient starvation, in a subpopulation of cells. In many cases, the molecular mechanisms underlying persistence are still unknown. However, there is growing evidence that, in enterobacteria, both stochastically and environmentally induced persistence are controlled by the second messenger (p)ppGpp...
November 5, 2016: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
Brian S DeDecker
Current gene synthesis methods often incorporate a PCR-amplifying step in order to yield sufficient final product that is detectable and resolvable from multiple off-products. This amplification step can cause stochastic sampling effects that propagate errors during the synthesis and lower the variability when applied towards the construction of randomized libraries. We present the method for polymerase step reaction (PSR), a simple DNA polymerase-based gene synthesis reaction that assembles DNA oligonucleotides in a unidirectional fashion without the need for a PCR-type amplification (Lee et al...
2017: Methods in Molecular Biology
Björn Reinius, Jeff E Mold, Daniel Ramsköld, Qiaolin Deng, Per Johnsson, Jakob Michaëlsson, Jonas Frisén, Rickard Sandberg
Cellular heterogeneity can emerge from the expression of only one parental allele. However, it has remained controversial whether, or to what degree, random monoallelic expression of autosomal genes (aRME) is mitotically inherited (clonal) or stochastic (dynamic) in somatic cells, particularly in vivo. Here we used allele-sensitive single-cell RNA-seq on clonal primary mouse fibroblasts and freshly isolated human CD8(+) T cells to dissect clonal and dynamic monoallelic expression patterns. Dynamic aRME affected a considerable portion of the cells' transcriptomes, with levels dependent on the cells' transcriptional activity...
September 26, 2016: Nature Genetics
Heng Xu, Samuel O Skinner, Anna Marie Sokac, Ido Golding
The stochastic kinetics of transcription is typically inferred from the distribution of RNA numbers in individual cells. However, cellular RNA reflects additional processes downstream of transcription, hampering this analysis. In contrast, nascent (actively transcribed) RNA closely reflects the kinetics of transcription. We present a theoretical model for the stochastic kinetics of nascent RNA, which we solve to obtain the probability distribution of nascent RNA per gene. The model allows us to evaluate the kinetic parameters of transcription from single-cell measurements of nascent RNA...
September 16, 2016: Physical Review Letters
Pavol Bokes, Abhyudai Singh
Inside individual cells, expression of genes is stochastic across organisms ranging from bacterial to human cells. A ubiquitous feature of stochastic expression is burst-like synthesis of gene products, which drives considerable intercellular variability in protein levels across an isogenic cell population. One common mechanism by which cells control such stochasticity is negative feedback regulation, where a protein inhibits its own synthesis. For a single gene that is expressed in bursts, negative feedback can affect the burst frequency or the burst size...
September 24, 2016: Journal of Mathematical Biology
Jin Chen, Junhong Choi, Seán E O'Leary, Arjun Prabhakar, Alexey Petrov, Rosslyn Grosely, Elisabetta Viani Puglisi, Joseph D Puglisi
Translation of proteins by the ribosome regulates gene expression, with recent results underscoring the importance of translational control. Misregulation of translation underlies many diseases, including cancer and many genetic diseases. Decades of biochemical and structural studies have delineated many of the mechanistic details in prokaryotic translation, and sketched the outlines of eukaryotic translation. However, translation may not proceed linearly through a single mechanistic pathway, but likely involves multiple pathways and branchpoints...
January 2016: Quarterly Reviews of Biophysics
Sinan Uğur Umu, Anthony M Poole, Renwick Cj Dobson, Paul P Gardner
A critical assumption of gene expression analysis is that mRNA abundances broadly correlate with protein abundance, but these two are often imperfectly correlated. Some of the discrepancy can be accounted for by two important mRNA features: codon usage and mRNA secondary structure. We present a new global factor, called mRNA:ncRNA avoidance, and provide evidence that avoidance increases translational efficiency. We also demonstrate a strong selection for the avoidance of stochastic mRNA:ncRNA interactions across prokaryotes, and that these have a greater impact on protein abundance than mRNA structure or codon usage...
2016: ELife
Nicolas Perrin
Sex-determining factors are usually assumed to be either genetic or environmental. The present paper aims at drawing attention to the potential contribution of developmental noise, an important but often-neglected component of phenotypic variance. Mutual inhibitions between male and female pathways make sex a bistable equilibrium, such that random fluctuations in the expression of genes at the top of the cascade are sufficient to drive individual development toward one or the other stable state. Evolutionary modeling shows that stochastic sex determinants should resist elimination by genetic or environmental sex determinants under ecologically meaningful settings...
September 19, 2016: BioEssays: News and Reviews in Molecular, Cellular and Developmental Biology
Darren J Parris, Rohan M Brooker, Michael A Morgan, Danielle L Dixson, Frank J Stewart
The Pomacentridae (damselfish) and Apogonidae (cardinalfish) are among the most common fish families on coral reefs and in the aquarium trade. Members of both families undergo a pelagic larvae phase prior to settlement on the reef, where adults play key roles in benthic habitat structuring and trophic interactions. Fish-associated microbial communities (microbiomes) significantly influence fish health and ecology, yet little is known of how microbiomes change with life stage. We quantified the taxonomic (16S rRNA gene) composition of whole gut microbiomes from ten species of damselfish and two species of cardinalfish from Lizard Island, Australia, focusing specifically on comparisons between pelagic larvae prior to settlement on the reef versus post-settlement juvenile and adult individuals...
2016: PeerJ
Sayuri K Hahl, Andreas Kremling
In the mathematical modeling of biochemical reactions, a convenient standard approach is to use ordinary differential equations (ODEs) that follow the law of mass action. However, this deterministic ansatz is based on simplifications; in particular, it neglects noise, which is inherent to biological processes. In contrast, the stochasticity of reactions is captured in detail by the discrete chemical master equation (CME). Therefore, the CME is frequently applied to mesoscopic systems, where copy numbers of involved components are small and random fluctuations are thus significant...
2016: Frontiers in Genetics
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