Publications by authors named "Ala Trusina"

35 Publications

Establishment of heterochromatin in domain-size-dependent bursts.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Department of Biology, University of Copenhagen, Copenhagen 2200, Denmark

Methylation of histone H3K9 is a hallmark of epigenetic silencing in eukaryotes. Nucleosome modifications often rely on positive feedback where enzymes are recruited by modified nucleosomes. A combination of local and global feedbacks has been proposed to account for some dynamic properties of heterochromatin, but the range at which the global feedbacks operate and the exact mode of heterochromatin propagation are not known. We investigated these questions in fission yeast. Guided by mathematical modeling, we incrementally increased the size of the mating-type region and profiled heterochromatin establishment over time. We observed exponential decays in the proportion of cells with active reporters, with rates that decreased with domain size. Establishment periods varied from a few generations in wild type to >200 generations in the longest region examined, and highly correlated silencing of two reporters located outside the nucleation center was observed. On a chromatin level, this indicates that individual regions are silenced in sudden bursts. Mathematical modeling accounts for these bursts if heterochromatic nucleosomes facilitate a deacetylation or methylation reaction at long range, in a distance-independent manner. A likely effector of three-dimensional interactions is the evolutionarily conserved Swi6 H3K9me reader, indicating the bursting behavior might be a general mode of heterochromatin propagation.
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http://dx.doi.org/10.1073/pnas.2022887118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053981PMC
April 2021

Model to Link Cell Shape and Polarity with Organogenesis.

iScience 2020 Feb 11;23(2):100830. Epub 2020 Jan 11.

Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark. Electronic address:

How do flat sheets of cells form gut and neural tubes? Across systems, several mechanisms are at play: cells wedge, form actomyosin cables, or intercalate. As a result, the cell sheet bends, and the tube elongates. It is unclear to what extent each mechanism can drive tube formation on its own. To address this question, we computationally probe if one mechanism, either cell wedging or intercalation, may suffice for the entire sheet-to-tube transition. Using a physical model with epithelial cells represented by polarized point particles, we show that either cell intercalation or wedging alone can be sufficient and that each can both bend the sheet and extend the tube. When working in parallel, the two mechanisms increase the robustness of the tube formation. The successful simulations of the key features in Drosophila salivary gland budding, sea urchin gastrulation, and mammalian neurulation support the generality of our results.
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http://dx.doi.org/10.1016/j.isci.2020.100830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994644PMC
February 2020

Self-assembly, buckling and density-invariant growth of three-dimensional vascular networks.

J R Soc Interface 2019 10 23;16(159):20190517. Epub 2019 Oct 23.

Niels Bohr Institute, University of Copenhagen, 2100 Copenhagen, Denmark.

The experimental actualization of organoids modelling organs from brains to pancreases has revealed that much of the diverse morphologies of organs are emergent properties of simple intercellular 'rules' and not the result of top-down orchestration. In contrast to other organs, the initial plexus of the vascular system is formed by aggregation of cells in the process known as vasculogenesis. Here we study this self-assembling process of blood vessels in three dimensions through a set of simple rules that align intercellular apical-basal and planar cell polarity. We demonstrate that a fully connected network of tubes emerges above a critical initial density of cells. Through planar cell polarity, our model demonstrates convergent extension, and this polarity furthermore allows for both morphology-maintaining growth and growth-induced buckling. We compare this buckling with the special vasculature of the islets of Langerhans in the pancreas and suggest that the mechanism behind the vascular density-maintaining growth of these islets could be the result of growth-induced buckling.
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http://dx.doi.org/10.1098/rsif.2019.0517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6833333PMC
October 2019

Chaperone-mediated reflux of secretory proteins to the cytosol during endoplasmic reticulum stress.

Proc Natl Acad Sci U S A 2019 06 17;116(23):11291-11298. Epub 2019 May 17.

Department of Medicine, University of California, San Francisco, CA 94143;

Diverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such "ER stress," we employed an ER-targeted, redox-responsive, green fluorescent protein-eroGFP-that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress regimes cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to "reflux" back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in , we show that ER protein reflux during ER stress requires specific chaperones and cochaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.
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http://dx.doi.org/10.1073/pnas.1904516116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561268PMC
June 2019

The fitness cost and benefit of phase-separated protein deposits.

Mol Syst Biol 2019 04 8;15(4):e8075. Epub 2019 Apr 8.

Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

Phase separation of soluble proteins into insoluble deposits is associated with numerous diseases. However, protein deposits can also function as membrane-less compartments for many cellular processes. What are the fitness costs and benefits of forming such deposits in different conditions? Using a model protein that phase-separates into deposits, we distinguish and quantify the fitness contribution due to the loss or gain of protein function and deposit formation in yeast. The environmental condition and the cellular demand for the protein function emerge as key determinants of fitness. Protein deposit formation can influence cell-to-cell variation in free protein abundance between individuals of a cell population (i.e., gene expression noise). This results in variable manifestation of protein function and a continuous range of phenotypes in a cell population, favoring survival of some individuals in certain environments. Thus, protein deposit formation by phase separation might be a mechanism to sense protein concentration in cells and to generate phenotypic variability. The selectable phenotypic variability, previously described for prions, could be a general property of proteins that can form phase-separated assemblies and may influence cell fitness.
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http://dx.doi.org/10.15252/msb.20178075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452874PMC
April 2019

Theoretical tool bridging cell polarities with development of robust morphologies.

Elife 2018 11 27;7. Epub 2018 Nov 27.

Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.

Despite continual renewal and damages, a multicellular organism is able to maintain its complex morphology. How is this stability compatible with the complexity and diversity of living forms? Looking for answers at protein level may be limiting as diverging protein sequences can result in similar morphologies. Inspired by the progressive role of apical-basal and planar cell polarity in development, we propose that stability, complexity, and diversity are emergent properties in populations of proliferating polarized cells. We support our hypothesis by a theoretical approach, developed to effectively capture both types of polar cell adhesions. When applied to specific cases of development - gastrulation and the origins of folds and tubes - our theoretical tool suggests experimentally testable predictions pointing to the strength of polar adhesion, restricted directions of cell polarities, and the rate of cell proliferation to be major determinants of morphological diversity and stability.
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http://dx.doi.org/10.7554/eLife.38407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286147PMC
November 2018

Stochastic priming and spatial cues orchestrate heterogeneous clonal contribution to mouse pancreas organogenesis.

Nat Commun 2017 09 19;8(1):605. Epub 2017 Sep 19.

DanStem, University of Copenhagen, 3B Blegdamsvej, DK-2200, Copenhagen N, Denmark.

Spatiotemporal balancing of cellular proliferation and differentiation is crucial for postnatal tissue homoeostasis and organogenesis. During embryonic development, pancreatic progenitors simultaneously proliferate and differentiate into the endocrine, ductal and acinar lineages. Using in vivo clonal analysis in the founder population of the pancreas here we reveal highly heterogeneous contribution of single progenitors to organ formation. While some progenitors are bona fide multipotent and contribute progeny to all major pancreatic cell lineages, we also identify numerous unipotent endocrine and ducto-endocrine bipotent clones. Single-cell transcriptional profiling at E9.5 reveals that endocrine-committed cells are molecularly distinct, whereas multipotent and bipotent progenitors do not exhibit different expression profiles. Clone size and composition support a probabilistic model of cell fate allocation and in silico simulations predict a transient wave of acinar differentiation around E11.5, while endocrine differentiation is proportionally decreased. Increased proliferative capacity of outer progenitors is further proposed to impact clonal expansion.
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http://dx.doi.org/10.1038/s41467-017-00258-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5605525PMC
September 2017

Impact of Zygosity on Bimodal Phenotype Distributions.

Biophys J 2017 Jul;113(1):148-156

Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain. Electronic address:

Allele number, or zygosity, is a clear determinant of gene expression in diploid cells. However, the relationship between the number of copies of a gene and its expression can be hard to anticipate, especially when the gene in question is embedded in a regulatory circuit that contains feedback. Here, we study this question making use of the natural genetic variability of human populations, which allows us to compare the expression profiles of a receptor protein in natural killer cells among donors infected with human cytomegalovirus with one or two copies of the allele. Crucially, the distribution of gene expression in many of the donors is bimodal, which indicates the presence of a positive feedback loop somewhere in the regulatory environment of the gene. Three separate gene-circuit models differing in the location of the positive feedback loop with respect to the gene can all reproduce the homozygous data. However, when the resulting fitted models are applied to the hemizygous donors, one model (the one with the positive feedback located at the level of gene transcription) is superior in describing the experimentally observed gene-expression profile. In that way, our work shows that zygosity can help us relate the structure and function of gene regulatory networks.
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http://dx.doi.org/10.1016/j.bpj.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5510722PMC
July 2017

Four simple rules that are sufficient to generate the mammalian blastocyst.

PLoS Biol 2017 Jul 12;15(7):e2000737. Epub 2017 Jul 12.

StemPhys, Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.

Early mammalian development is both highly regulative and self-organizing. It involves the interplay of cell position, predetermined gene regulatory networks, and environmental interactions to generate the physical arrangement of the blastocyst with precise timing. However, this process occurs in the absence of maternal information and in the presence of transcriptional stochasticity. How does the preimplantation embryo ensure robust, reproducible development in this context? It utilizes a versatile toolbox that includes complex intracellular networks coupled to cell-cell communication, segregation by differential adhesion, and apoptosis. Here, we ask whether a minimal set of developmental rules based on this toolbox is sufficient for successful blastocyst development, and to what extent these rules can explain mutant and experimental phenotypes. We implemented experimentally reported mechanisms for polarity, cell-cell signaling, adhesion, and apoptosis as a set of developmental rules in an agent-based in silico model of physically interacting cells. We find that this model quantitatively reproduces specific mutant phenotypes and provides an explanation for the emergence of heterogeneity without requiring any initial transcriptional variation. It also suggests that a fixed time point for the cells' competence of fibroblast growth factor (FGF)/extracellular signal-regulated kinase (ERK) sets an embryonic clock that enables certain scaling phenomena, a concept that we evaluate quantitatively by manipulating embryos in vitro. Based on these observations, we conclude that the minimal set of rules enables the embryo to experiment with stochastic gene expression and could provide the robustness necessary for the evolutionary diversification of the preimplantation gene regulatory network.
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http://dx.doi.org/10.1371/journal.pbio.2000737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507476PMC
July 2017

Evolution of a G protein-coupled receptor response by mutations in regulatory network interactions.

Nat Commun 2016 08 4;7:12344. Epub 2016 Aug 4.

Department of Cell and Systems Biology, University of Toronto, 25 Harbord Street, Toronto, Ontario, Canada M5S 3G5.

All cellular functions depend on the concerted action of multiple proteins organized in complex networks. To understand how selection acts on protein networks, we used the yeast mating receptor Ste2, a pheromone-activated G protein-coupled receptor, as a model system. In Saccharomyces cerevisiae, Ste2 is a hub in a network of interactions controlling both signal transduction and signal suppression. Through laboratory evolution, we obtained 21 mutant receptors sensitive to the pheromone of a related yeast species and investigated the molecular mechanisms behind this newfound sensitivity. While some mutants show enhanced binding affinity to the foreign pheromone, others only display weakened interactions with the network's negative regulators. Importantly, the latter changes have a limited impact on overall pathway regulation, despite their considerable effect on sensitivity. Our results demonstrate that a new receptor-ligand pair can evolve through network-altering mutations independently of receptor-ligand binding, and suggest a potential role for such mutations in disease.
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http://dx.doi.org/10.1038/ncomms12344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976203PMC
August 2016

Asymmetric Damage Segregation Constitutes an Emergent Population-Level Stress Response.

Cell Syst 2016 Aug 14;3(2):187-198. Epub 2016 Jul 14.

Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen, Denmark. Electronic address:

Asymmetric damage segregation (ADS) is a mechanism for increasing population fitness through non-random, asymmetric partitioning of damaged macromolecules at cell division. ADS has been reported across multiple organisms, though the measured effects on fitness of individuals are often small. Here, we introduce a cell-lineage-based framework that quantifies the population-wide effects of ADS and then verify our results experimentally in E. coli under heat and antibiotic stress. Using an experimentally validated mathematical model, we find that the beneficial effect of ADS increases with stress. In effect, low-damage subpopulations divide faster and amplify within the population acting like a positive feedback loop whose strength scales with stress. Analysis of protein aggregates shows that the degree of asymmetric inheritance is damage dependent in single cells. Together our results indicate that, despite small effects in single cell, ADS exerts a strong beneficial effect on the population level and arises from the redistribution of damage within a population, through both single-cell and population-level feedback.
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http://dx.doi.org/10.1016/j.cels.2016.06.008DOI Listing
August 2016

Nucleation and spreading of a heterochromatic domain in fission yeast.

Nat Commun 2016 05 11;7:11518. Epub 2016 May 11.

Department of Biology, University of Copenhagen, BioCenter, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.

Outstanding questions in the chromatin field bear on how large heterochromatin domains are formed in space and time. Positive feedback, where histone-modifying enzymes are attracted to chromosomal regions displaying the modification they catalyse, is believed to drive the formation of these domains; however, few quantitative studies are available to assess this hypothesis. Here we quantified the de novo establishment of a naturally occurring ∼20-kb heterochromatin domain in fission yeast through single-cell analyses, measuring the kinetics of heterochromatin nucleation in a region targeted by RNAi and its subsequent expansion. We found that nucleation of heterochromatin is stochastic and can take from one to ten cell generations. Further silencing of the full region takes another one to ten generations. Quantitative modelling of the observed kinetics emphasizes the importance of local feedback, where a nucleosome-bound enzyme modifies adjacent nucleosomes, combined with a feedback where recruited enzymes can act at a distance.
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http://dx.doi.org/10.1038/ncomms11518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865850PMC
May 2016

Dynamics of the DNA repair proteins WRN and BLM in the nucleoplasm and nucleoli.

Eur Biophys J 2014 Nov 14;43(10-11):509-16. Epub 2014 Aug 14.

CMOL, Niels Bohr Institute, University of Copenhagen, 2100, Copenhagen, Denmark,

We have investigated the mobility of two EGFP-tagged DNA repair proteins, WRN and BLM. In particular, we focused on the dynamics in two locations, the nucleoli and the nucleoplasm. We found that both WRN and BLM use a "DNA-scanning" mechanism, with rapid binding-unbinding to DNA resulting in effective diffusion. In the nucleoplasm WRN and BLM have effective diffusion coefficients of 1.62 and 1.34 μm(2)/s, respectively. Likewise, the dynamics in the nucleoli are also best described by effective diffusion, but with diffusion coefficients a factor of ten lower than in the nucleoplasm. From this large reduction in diffusion coefficient we were able to classify WRN and BLM as DNA damage scanners. In addition to WRN and BLM we also classified other DNA damage proteins and found they all fall into one of two categories. Either they are scanners, similar to WRN and BLM, with very low diffusion coefficients, suggesting a scanning mechanism, or they are almost freely diffusing, suggesting that they interact with DNA only after initiation of a DNA damage response.
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http://dx.doi.org/10.1007/s00249-014-0981-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576897PMC
November 2014

Stress induced telomere shortening: longer life with less mutations?

Authors:
Ala Trusina

BMC Syst Biol 2014 Mar 1;8:27. Epub 2014 Mar 1.

Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, DK 2100, Copenhagen, Denmark.

Background: Mutations accumulate as a result of DNA damage and imperfect DNA repair machinery. In higher eukaryotes the accumulation and spread of mutations is limited in two primary ways: through p53-mediated programmed cell death and cellular senescence mediated by telomeres. Telomeres shorten at every cell division and cell stops dividing once the shortest telomere reaches a critical length. It has been shown that the rate of telomere attrition is accelerated when cells are exposed to DNA damaging agents. However the implications of this mechanism are not fully understood.

Results: With the help of in silico model we investigate the effect of genotoxic stress on telomere attrition and apoptosis in a population of non-identical replicating cells. When comparing the populations of cells with constant vs. stress-induced rate of telomere shortening we find that stress induced telomere shortening (SITS) increases longevity while reducing mutation rate. Interestingly, however, the effect takes place only when genotoxic stresses (e.g. reactive oxygen species due to metabolic activity) are distributed non-equally among cells.

Conclusions: Our results for the first time show how non-equal distribution of metabolic load (and associated genotoxic stresses) combined with stress induced telomere shortening can delay aging and minimize mutations.
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http://dx.doi.org/10.1186/1752-0509-8-27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4015310PMC
March 2014

Two portable recombination enhancers direct donor choice in fission yeast heterochromatin.

PLoS Genet 2013 Oct 24;9(10):e1003762. Epub 2013 Oct 24.

Department of Biology, University of Copenhagen, BioCenter, Copenhagen, Denmark.

Mating-type switching in fission yeast results from gene conversions of the active mat1 locus by heterochromatic donors. mat1 is preferentially converted by mat2-P in M cells and by mat3-M in P cells. Here, we report that donor choice is governed by two portable recombination enhancers capable of promoting use of their adjacent cassette even when they are transposed to an ectopic location within the mat2-mat3 heterochromatic domain. Cells whose silent cassettes are swapped to mat2-M mat3-P switch mating-type poorly due to a defect in directionality but cells whose recombination enhancers were transposed together with the cassette contents switched like wild type. Trans-acting mutations that impair directionality affected the wild-type and swapped cassettes in identical ways when the recombination enhancers were transposed together with their cognate cassette, showing essential regulatory steps occur through the recombination enhancers. Our observations lead to a model where heterochromatin biases competitions between the two recombination enhancers to achieve directionality.
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http://dx.doi.org/10.1371/journal.pgen.1003762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812072PMC
October 2013

Noisy transcription factor NF-κB oscillations stabilize and sensitize cytokine signaling in space.

Phys Rev E Stat Nonlin Soft Matter Phys 2013 Feb 5;87(2):022702. Epub 2013 Feb 5.

Niels Bohr Institute, University of Copenhagen, DK-2100 Copenhagen, Denmark.

NF-κB is a major transcription factor mediating inflammatory response. In response to a pro-inflammatory stimulus, it exhibits a characteristic response-a pulse followed by noisy oscillations in concentrations of considerably smaller amplitude. NF-κB is an important mediator of cellular communication, as it is both activated by and upregulates production of cytokines, signals used by white blood cells to find the source of inflammation. While the oscillatory dynamics of NF-κB has been extensively investigated both experimentally and theoretically, the role of the noise and the lower secondary amplitude has not been addressed. We use a cellular automaton model to address these issues in the context of spatially distributed communicating cells. We find that noisy secondary oscillations stabilize concentric wave patterns, thus improving signal quality. Furthermore, both lower secondary amplitude as well as noise in the oscillation period might be working against chronic inflammation, the state of self-sustained and stimulus-independent excitations. Our findings suggest that the characteristic irregular secondary oscillations of lower amplitude are not accidental. On the contrary, they might have evolved to increase robustness of the inflammatory response and the system's ability to return to a pre-stimulated state.
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http://dx.doi.org/10.1103/PhysRevE.87.022702DOI Listing
February 2013

Circuit architecture explains functional similarity of bacterial heat shock responses.

Phys Biol 2012 Dec 31;9(6):066003. Epub 2012 Oct 31.

Cybermedia Center, Osaka University, Toyonaka, Osaka 560-0043, Japan.

Heat shock response is a stress response to temperature changes and a consecutive increase in amounts of unfolded proteins. To restore homeostasis, cells upregulate chaperones facilitating protein folding by means of transcription factors (TFs). We here investigate two heat shock systems: one characteristic to gram negative bacteria, mediated by transcriptional activator σ(32) in E. coli, and another characteristic to gram positive bacteria, mediated by transcriptional repressor HrcA in L. lactis. We construct simple mathematical models of the two systems focusing on the negative feedbacks, where free chaperones suppress σ(32) activation in the former, while they activate HrcA repression in the latter. We demonstrate that both systems, in spite of the difference at the TF regulation level, are capable of showing very similar heat shock dynamics. We find that differences in regulation impose distinct constraints on chaperone-TF binding affinities: the binding constant of free σ(32) to chaperone DnaK, known to be in 100 nM range, set the lower limit of amount of free chaperone that the system can sense the change at the heat shock, while the binding affinity of HrcA to chaperone GroE set the upper limit and have to be rather large extending into the micromolar range.
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http://dx.doi.org/10.1088/1478-3975/9/6/066003DOI Listing
December 2012

IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress.

Cell Metab 2012 Aug;16(2):250-64

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

When unfolded proteins accumulate to irremediably high levels within the endoplasmic reticulum (ER), intracellular signaling pathways called the unfolded protein response (UPR) become hyperactivated to cause programmed cell death. We discovered that thioredoxin-interacting protein (TXNIP) is a critical node in this "terminal UPR." TXNIP becomes rapidly induced by IRE1α, an ER bifunctional kinase/endoribonuclease (RNase). Hyperactivated IRE1α increases TXNIP mRNA stability by reducing levels of a TXNIP destabilizing microRNA, miR-17. In turn, elevated TXNIP protein activates the NLRP3 inflammasome, causing procaspase-1 cleavage and interleukin 1β (IL-1β) secretion. Txnip gene deletion reduces pancreatic β cell death during ER stress and suppresses diabetes caused by proinsulin misfolding in the Akita mouse. Finally, small molecule IRE1α RNase inhibitors suppress TXNIP production to block IL-1β secretion. In summary, the IRE1α-TXNIP pathway is used in the terminal UPR to promote sterile inflammation and programmed cell death and may be targeted to develop effective treatments for cell degenerative diseases.
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http://dx.doi.org/10.1016/j.cmet.2012.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4014071PMC
August 2012

Fragile DNA repair mechanism reduces ageing in multicellular model.

PLoS One 2012 2;7(5):e36018. Epub 2012 May 2.

Niels Bohr Institute/CMOL, University of Copenhagen, Copenhagen, Denmark.

DNA damages, as well as mutations, increase with age. It is believed that these result from increased genotoxic stress and decreased capacity for DNA repair. The two causes are not independent, DNA damage can, for example, through mutations, compromise the capacity for DNA repair, which in turn increases the amount of unrepaired DNA damage. Despite this vicious circle, we ask, can cells maintain a high DNA repair capacity for some time or is repair capacity bound to continuously decline with age? We here present a simple mathematical model for ageing in multicellular systems where cells subjected to DNA damage can undergo full repair, go apoptotic, or accumulate mutations thus reducing DNA repair capacity. Our model predicts that at the tissue level repair rate does not continuously decline with age, but instead has a characteristic extended period of high and non-declining DNA repair capacity, followed by a rapid decline. Furthermore, the time of high functionality increases, and consequently slows down the ageing process, if the DNA repair mechanism itself is vulnerable to DNA damages. Although counterintuitive at first glance, a fragile repair mechanism allows for a faster removal of compromised cells, thus freeing the space for healthy peers. This finding might be a first step toward understanding why a mutation in single DNA repair protein (e.g. Wrn or Blm) is not buffered by other repair proteins and therefore, leads to severe ageing disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0036018PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342328PMC
September 2012

Conditional cooperativity in toxin-antitoxin regulation prevents random toxin activation and promotes fast translational recovery.

Nucleic Acids Res 2012 Aug 11;40(14):6424-34. Epub 2012 Apr 11.

Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, DK-2100 Copenhagen, Denmark.

Many toxin-antitoxin (TA) loci are known to strongly repress their own transcription. This auto-inhibition is often called 'conditional cooperativity' as it relies on cooperative binding of TA complexes to operator DNA that occurs only when toxins are in a proper stoichiometric relationship with antitoxins. There has recently been an explosion of interest in TA systems due to their role in bacterial persistence, however the role of conditional cooperativity is still unclear. We reveal the biological function of conditional cooperativity by constructing a mathematical model of the well studied TA system, relBE of Escherichia coli. We show that the model with the in vivo and in vitro established parameters reproduces experimentally observed response to nutritional stress. We further demonstrate that conditional cooperativity stabilizes the level of antitoxin in rapidly growing cells such that random induction of relBE is minimized. At the same time it enables quick removal of free toxin when the starvation is terminated.
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http://dx.doi.org/10.1093/nar/gks297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413109PMC
August 2012

Analyzing inflammatory response as excitable media.

Phys Rev E Stat Nonlin Soft Matter Phys 2011 Nov 18;84(5 Pt 1):051913. Epub 2011 Nov 18.

Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.

The regulatory system of the transcription factor NF-κB plays a great role in many cell functions, including inflammatory response. Interestingly, the NF-κB system is known to up-regulate production of its own triggering signal-namely, inflammatory cytokines such as TNF, IL-1, and IL-6. In this paper we investigate a previously presented model of the NF-κB, which includes both spatial effects and the positive feedback from cytokines. The model exhibits the properties of an excitable medium and has the ability to propagate waves of high cytokine concentration. These waves represent an optimal way of sending an inflammatory signal through the tissue as they create a chemotactic signal able to recruit neutrophils to the site of infection. The simple model displays three qualitatively different states; low stimuli leads to no or very little response. Intermediate stimuli leads to reoccurring waves of high cytokine concentration. Finally, high stimuli leads to a sustained high cytokine concentration, a scenario which is toxic for the tissue cells and corresponds to chronic inflammation. Due to the few variables of the simple model, we are able to perform a phase-space analysis leading to a detailed understanding of the functional form of the model and its limitations. The spatial effects of the model contribute to the robustness of the cytokine wave formation and propagation.
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http://dx.doi.org/10.1103/PhysRevE.84.051913DOI Listing
November 2011

Ecosystems with mutually exclusive interactions self-organize to a state of high diversity.

Phys Rev Lett 2011 Oct 25;107(18):188101. Epub 2011 Oct 25.

Niels Bohr Institute/CMOL, University of Copenhagen, Blegdamsvej-17, DK2100, Copenhagen, Denmark.

Ecological systems comprise an astonishing diversity of species that cooperate or compete with each other forming complex mutual dependencies. The minimum requirements to maintain a large species diversity on long time scales are in general unknown. Using lichen communities as an example, we propose a model for the evolution of mutually excluding organisms that compete for space. We suggest that chainlike or cyclic invasions open for creation of spatially separated subpopulations that subsequently can lead to increased diversity. In contrast to its nonspatial counterpart, our model predicts robust coexistence of a large number of species. It is demonstrated that large species diversity can be obtained on evolutionary time scales, provided that interactions between species have spatial constraints. In particular, a phase transition to a sustainable state of high diversity is identified.
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http://dx.doi.org/10.1103/PhysRevLett.107.188101DOI Listing
October 2011

Targeted bacterial immunity buffers phage diversity.

J Virol 2011 Oct 3;85(20):10554-60. Epub 2011 Aug 3.

Center for Models of Life, Niels Bohr Institute, University of Copenhagen, Blegdamsvej 17, 2100 Copenhagen Ø, Denmark.

Bacteria have evolved diverse defense mechanisms that allow them to fight viral attacks. One such mechanism, the clustered, regularly interspaced, short palindromic repeat (CRISPR) system, is an adaptive immune system consisting of genetic loci that can take up genetic material from invasive elements (viruses and plasmids) and later use them to reject the returning invaders. It remains an open question how, despite the ongoing evolution of attack and defense mechanisms, bacteria and viral phages manage to coexist. Using a simple mathematical model and a two-dimensional numerical simulation, we found that CRISPR adaptive immunity allows for robust phage-bacterium coexistence even when the number of virus species far exceeds the capacity of CRISPR-encoded genetic memory. Coexistence is predicted to be a consequence of the presence of many interdependent species that stress but do not overrun the bacterial defense system.
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http://dx.doi.org/10.1128/JVI.05222-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187494PMC
October 2011

Modeling the NF-κB mediated inflammatory response predicts cytokine waves in tissue.

BMC Syst Biol 2011 Jul 19;5:115. Epub 2011 Jul 19.

Niels Bohr Institute, Copenhagen, Denmark.

Background: Waves propagating in "excitable media" is a reliable way to transmit signals in space. A fascinating example where living cells comprise such a medium is Dictyostelium D. which propagates waves of chemoattractant to attract distant cells. While neutrophils chemotax in a similar fashion as Dictyostelium D., it is unclear if chemoattractant waves exist in mammalian tissues and what mechanisms could propagate them.

Results: We propose that chemoattractant cytokine waves may naturally develop as a result of NF-κB response. Using a heuristic mathematical model of NF-κB-like circuits coupled in space we show that the known characteristics of NF-κB response favor cytokine waves.

Conclusions: While the propagating wave of cytokines is generally beneficial for inflammation resolution, our model predicts that there exist special conditions that can cause chronic inflammation and re-occurrence of acute inflammatory response.
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http://dx.doi.org/10.1186/1752-0509-5-115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152534PMC
July 2011

A minimal model for multiple epidemics and immunity spreading.

PLoS One 2010 Oct 18;5(10):e13326. Epub 2010 Oct 18.

Niels Bohr Institute/CMOL, Copenhagen, Denmark.

Pathogens and parasites are ubiquitous in the living world, being limited only by availability of suitable hosts. The ability to transmit a particular disease depends on competing infections as well as on the status of host immunity. Multiple diseases compete for the same resource and their fate is coupled to each other. Such couplings have many facets, for example cross-immunization between related influenza strains, mutual inhibition by killing the host, or possible even a mutual catalytic effect if host immunity is impaired. We here introduce a minimal model for an unlimited number of unrelated pathogens whose interaction is simplified to simple mutual exclusion. The model incorporates an ongoing development of host immunity to past diseases, while leaving the system open for emergence of new diseases. The model exhibits a rich dynamical behavior with interacting infection waves, leaving broad trails of immunization in the host population. This obtained immunization pattern depends only on the system size and on the mutation rate that initiates new diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0013326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956625PMC
October 2010

Modeling oscillatory control in NF-κB, p53 and Wnt signaling.

Curr Opin Genet Dev 2010 Dec 9;20(6):656-64. Epub 2010 Oct 9.

Center for Models of Life, Niels Bohr Institute, Copenhagen, Denmark.

Oscillations are commonly observed in cellular behavior and span a wide range of timescales, from seconds in calcium signaling to 24 hours in circadian rhythms. In between lie oscillations with time periods of 1-5 hours seen in NF-κB, p53 and Wnt signaling, which play key roles in the immune system, cell growth/death and embryo development, respectively. In the first part of this article, we provide a brief overview of simple deterministic models of oscillations. In particular, we explain the mechanism of saturated degradation that has been used to model oscillations in the NF-κB, p53 and Wnt systems. The second part deals with the potential physiological role of oscillations. We use the simple models described earlier to explore whether oscillatory signals can encode more information than steady-state signals. We then discuss a few simple genetic circuits that could decode information stored in the average, amplitude or frequency of oscillations. The presence of frequency-detector circuit downstream of NF-κB or p53 would be a strong clue that oscillations are important for the physiological response of these signaling systems.
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http://dx.doi.org/10.1016/j.gde.2010.08.008DOI Listing
December 2010

Defining network topologies that can achieve biochemical adaptation.

Cell 2009 Aug;138(4):760-73

Center for Theoretical Biology, Peking University, Beijing 100871, China..

Many signaling systems show adaptation-the ability to reset themselves after responding to a stimulus. We computationally searched all possible three-node enzyme network topologies to identify those that could perform adaptation. Only two major core topologies emerge as robust solutions: a negative feedback loop with a buffering node and an incoherent feedforward loop with a proportioner node. Minimal circuits containing these topologies are, within proper regions of parameter space, sufficient to achieve adaptation. More complex circuits that robustly perform adaptation all contain at least one of these topologies at their core. This analysis yields a design table highlighting a finite set of adaptive circuits. Despite the diversity of possible biochemical networks, it may be common to find that only a finite set of core topologies can execute a particular function. These design rules provide a framework for functionally classifying complex natural networks and a manual for engineering networks. For a video summary of this article, see the PaperFlick file with the Supplemental Data available online.
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http://dx.doi.org/10.1016/j.cell.2009.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068210PMC
August 2009

Rationalizing translation attenuation in the network architecture of the unfolded protein response.

Proc Natl Acad Sci U S A 2008 Dec 15;105(51):20280-5. Epub 2008 Dec 15.

California Institute for Quantitative Biosciences, University of California, San Francisco, CA 94158, USA.

Increased levels of unfolded proteins in the endoplasmic reticulum (ER) of all eukaryotes trigger the unfolded protein response (UPR). Lower eukaryotes solely use an ancient UPR mechanism, whereby they up-regulate ER-resident chaperones and other enzymatic activities to augment protein folding and enhance degradation of misfolded proteins. Metazoans have evolved an additional mechanism through which they attenuate translation of secretory pathway proteins by activating the ER protein kinase PERK. In mammalian professional secretory cells such as insulin-producing pancreatic beta-cells, PERK is highly abundant and crucial for proper functioning of the secretory pathway. Through a modeling approach, we propose explanations for why a translation attenuation (TA) mechanism may be critical for beta-cells, but is less important in nonsecretory cells and unnecessary in lower eukaryotes such as yeast. We compared the performance of a model UPR, both with and without a TA mechanism, by monitoring 2 variables: (i) the maximal increase in ER unfolded proteins during a response, and (ii) the accumulation of chaperones between 2 consecutive pulses of stress. We found that a TA mechanism is important for minimizing these 2 variables when the ER is repeatedly subjected to transient unfolded protein stresses and when it sustains a large flux of secretory pathway proteins which are both conditions encountered physiologically by pancreatic beta-cells. Low expression of PERK in nonsecretory cells, and its absence in yeast, can be rationalized by lower trafficking of secretory proteins through their ERs.
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http://dx.doi.org/10.1073/pnas.0803476105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603256PMC
December 2008

Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions.

Cell 2008 Nov 20;135(5):933-47. Epub 2008 Nov 20.

Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.

Disruption of protein folding in the endoplasmic reticulum (ER) causes unfolded proteins to accumulate, triggering the unfolded protein response (UPR). UPR outputs in turn decrease ER unfolded proteins to close a negative feedback loop. However, because it is infeasible to directly measure the concentration of unfolded proteins in vivo, cells are generically described as experiencing "ER stress" whenever the UPR is active. Because ER redox potential is optimized for oxidative protein folding, we reasoned that measureable redox changes should accompany unfolded protein accumulation. To test this concept, we employed fluorescent protein reporters to dynamically measure ER redox status and UPR activity in single cells. Using these tools, we show that diverse stressors, both experimental and physiological, compromise ER protein oxidation when UPR-imposed homeostatic control is lost. Using genetic analysis we uncovered redox heterogeneities in isogenic cell populations, and revealed functional interlinks between ER protein folding, modification, and quality control systems.
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http://dx.doi.org/10.1016/j.cell.2008.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739138PMC
November 2008

Aging mechanism as the "down side" of adaptation: a network approach.

J Theor Biol 2008 Jan 19;250(1):66-74. Epub 2007 Sep 19.

Center for Models of Life, The Niels Bohr Institute, Copenhagen, Denmark.

Many diverse hypotheses on aging are in play. All from "aging genes" over decreasing telomere length to increased level of gene mutations has been suggested to determine an organism's lifespan, but no unifying theory exists. As part of a growing interest toward more integrative approaches in the field we propose a simplistic model based on the "use-it-or-lose-it" concept: we hypothesize that biological aging is a systemic property and the down side of adaptation in complex biological networks at various levels of organization: from brain over the immune system to specialized tissues or organs. The simple dynamical model undergoes three phases during its lifetime: (1) general plasticity (childhood), (2) optimization/adaptation to given conditions (youth and adolescence) and (3) steady state associated with high rigidity (aging). Furthermore, our model mimics recent data on the dynamics of the immune system during aging and, although simplistic, thus captures essential characteristics of the aging process. Finally, we discuss the abstract model in relation to current knowledge on aging and propose experimental setups for testing some of the theoretical predictions.
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http://dx.doi.org/10.1016/j.jtbi.2007.09.016DOI Listing
January 2008