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Results for “systems biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 991 records · Page 55Linked to original sources

bioRxiv2017

Predictive model identifies strategies to enhance TSP1-mediated apoptosis signaling

This study explores strategies to enhance thrombospondin-1 (TSP1) induced apoptosis in endothelial cells, an important function that contributes to TSP1s anti-angiogenic effect. We established a mathematical model of TSP1-mediated intracellular signaling via the CD36 receptor. This model was used to investigate the effects of several approaches to perturb the TSP1-CD36 signaling network. Model simulations predict the population-based response to strategies to enhance TSP1-mediated apoptosis, such as downregulating the apoptosis inhibitor XIAP and inhibiting phosphatase activity. The model also postulates a new mechanism of low dosage doxorubicin treatment in combination with TSP1 stimulation. Using computational analysis, we predict which cells will undergo apoptosis, based on the initial intracellular concentrations of particular signaling species. Overall, the modeling framework predicts molecular strategies that increase TSP1-mediated apoptosis, which is useful in many disease settings.

systems biology↗

bioRxiv2017

Simulating the Idling Behavior of Escherichia Coli

Until now, it is not known how the motors of E. coli reverse the direction of rotation, mostly simultaneously. If the C-ring is bistable and if the number of bound CheY-P depends on the direction of rotation, there is a strong variation in the concentration of CheY-P in the cytoplasm. Then, the synchronous changeover can be explained without further additional assumptions.

systems biology↗

bioRxiv2017

A Yeast Global Genetic Screen Reveals that Metformin Induces an Iron Deficiency-Like State

We report here a simple and global strategy to map out gene functions and target pathways of drugs, toxins or other small molecules based on \"homomer dynamics\" Protein-fragment Complementation Assays (hdPCA). hdPCA measures changes in self-association (homomerization) of over 3,500 yeast proteins in yeast grown under different conditions. hdPCA complements genetic interaction measurements while eliminating confounding effects of gene ablation. We demonstrate that hdPCA accurately predicts the effects of two longevity and health-span-affecting drugs, immunosuppressant rapamycin and type II diabetes drug metformin, on cellular pathways. We also discovered an unsuspected global cellular response to metformin that resembles iron deficiency. This discovery opens a new avenue to investigate molecular mechanisms for the prevention or treatments of diabetes, cancers and other chronic diseases of aging.

systems biology↗

bioRxiv2017

The Cell-Cycle Transcriptional Network Generates and Transmits a Pulse of Transcription Once Each Cell Cycle

Multiple studies have suggested the critical roles of cyclin-dependent kinases (CDKs) as well as a transcription factor (TF) network in generating the robust cell-cycle transcriptional program. However, the precise mechanisms by which these components function together in the gene regulatory network remain unclear. Here we show that the TF network can generate and transmit a \"pulse\" of transcription independently of CDK oscillations. The premature firing of the transcriptional pulse is prevented by early G1 inhibitors, including transcriptional corepressors and the E3 ubiquitin ligase complex APCCdh1. We demonstrate that G1 cyclin-CDKs facilitate the activation and accumulation of TF proteins in S/G2/M phases through inhibiting G1 transcriptional corepressors (Whi5 and Stb1) and APCCdh1, thereby promoting the initiation and propagation of the pulse by the TF network. These findings suggest a unique oscillatory mechanism in which global phase-specific transcription emerges from a pulse-generating network that fires once-and-only-once at the start of the cycle.

systems biology↗

bioRxiv2017

Cryo-EM reconstruction of AlfA from Bacillus subtilis reveals the structure of a simplified actin-like filament at 3.4 A resolution

Low copy-number plasmid pLS32 of Bacillus subtilis subsp. natto contains a partitioning system that ensures segregation of plasmid copies during cell division. The partitioning locus comprises actin-like protein AlfA, adaptor protein AlfB and the centromeric sequence parN. Similar to the ParMRC partitioning system from E. coli plasmid R1, AlfA filaments form actin-like double helical filaments that arrange into an antiparallel bipolar spindle, which attaches its growing ends to sister plasmids, through interactions with AlfB and parN. Since, compared with ParM and other actin-like proteins, AlfA is highly diverged in sequence, we determined the atomic structure of non-bundling AlfA filaments to 3.4 [A] resolution by cryo-EM. The structure reveals how the deletion of subdomain IIB of the canonical actin-fold has been accommodated by unique longitudinal and lateral contacts, whilst still enabling formation of left-handed, double helical, polar and staggered filaments that are architecturally similar to ParM. Through cryo-EM reconstruction of bundling AlfA filaments we obtained a pseudo-atomic model of AlfA doublets: the assembly of two filaments. The filaments are antiparallel, as required by the segregation mechanism, and exactly anti-phasic with 8-fold integer helical symmetry, to enable efficient doublet formation. The structure of AlfA filaments and doublets shows, in atomic detail, signs of the strong evolutionary pressure for simplicity, placed on plasmids: deletion of an entire domain of the actin fold is compensated by changes to all interfaces so that the required properties of polymerisation, nucleotide hydrolysis and antiparallel doublet formation are retained to fulfil the system's biological raison d'etre.\n\nSignificance StatementProtein filaments perform a vast array of functions inside almost all living cells. Actin-like proteins in archaea and bacteria have previously been found to form a surprising diversity of filament architectures, reflecting their divergent cellular roles. Actin-like AlfA is unique in that it is much smaller than all other filament forming actin-like proteins. With an atomic structure of the AlfA filament, obtained by high-resolution electron cryo-microscopy, we have revealed--at atomic level of detail--how AlfA filaments form dynamic filaments capable of transporting plasmid DNA in cells and how these filaments arrange into antiparallel bundles required for the segregation mechanism.

microbiology↗

bioRxiv2017

High Peak Density Artifacts in Fourier Transform Mass Spectra and their Effects on Data Analysis

Fourier-transform mass spectrometry (FT-MS) allows for the high-throughput and high-resolution detection of thousands of metabolites. Observed spectral features (peaks) that are not isotopologues do not directly correspond to known compounds and cannot be placed into existing metabolic networks. Spectral artifacts account for many of these unidentified peaks, and misassignments made to these artifact peaks can create large interpretative errors. Without accurate identification of artifactual features and correct assignment of real features, discerning their roles within living systems is effectively impossible.\n\nWe have observed three types of artifacts unique to FT-MS that often result in regions of abnormally high peak density (HPD), which we collectively refer to as HPD artifacts: i) fuzzy sites representing small regions of m/z space with a fuzzy appearance due to the extremely high number of peaks present; ii) ringing due to a very intense peak producing side bands of decreasing intensity that are symmetrically distributed around the main peak; and iii) partial ringing where only a subset of the side bands are observed for an intense peak. Fuzzy sites and partial ringing appear to be novel artifacts previously unreported in the literature and we hypothesize that all three artifact types derive from Fourier transformation-based issues. In some spectra, these artifacts account for roughly a third of the peaks present in the given spectrum. We have developed a set of tools to detect these artifacts and approaches to mitigate their effects on downstream analyses.

systems biology↗

bioRxiv2017

Distributed and dynamic intracellular organization of extracellular information

Although cells respond specifically to environments, how environmental identity is encoded intracellularly is not understood. Here we study this organization of information in budding yeast by estimating the mutual information between environmental transitions and the dynamics of nuclear translocation for ten transcription factors. Our method of estimation is general, scalable, and based on decoding from single cells. The dynamics of the transcription factors are necessary to encode the highest amounts of extracellular information, and we show that information is transduced through two channels: generalists (Msn2/4, Tod6/Dot6, Maf1, and Sfp1) can encode the nature of multiple stresses but only if stress is high; specialists (Hog1, Yap1, and Mig1/2) encode one particular stress, but do so more quickly and for a wider range of magnitudes. Each transcription factor reports differently, and it is only their collective response that distinguishes between multiple environmental states. Changes in the dynamics of the localization of transcription factors thus constitute a precise, distributed internal representation of extracellular change, and we predict that such multi-dimensional representations are common in cellular decision-making.\n\nSignificance StatementTo thrive in diverse environments, cells must represent extracellular change intracellularly despite stochastic biochemistry. Here we introduce a quantitative framework for investigating the organization of information within a cell. Combining single-cell measurements of intracellular dynamics with a new, scalable methodology for estimating mutual information between time-series and a discrete input, we demonstrate that extracellular information is encoded in the dynamics of the nuclear localization of transcription factors and that information is lost with alternative static statistics. Any one transcription factor is usually insufficient, but the collective dynamics of multiple transcription factors can represent complex extracellular change. We therefore show that a cells internal representation of its environment can be both distributed across diverse proteins and dynamically encoded.

systems biology↗

bioRxiv2017

Promoter architecture determines co-translational regulation of mRNA

Information that regulates gene expression is encoded throughout each gene but if different regulatory regions can be understood in isolation, or if they interact, is unknown. Here we measure mRNA levels for 10,000 open reading frames (ORFs) transcribed from either an inducible or constitutive promoter. We find that the strength of co-translational regulation on mRNA levels is determined by promoter architecture. Using a novel computational-genetic screen of 6402 RNA-seq experiments we identify the RNA helicase Dbp2 as the mechanism by which co-translational regulation is reduced specifically for inducible promoters. Finally, we find that for constitutive genes, but not inducible genes, most of the information encoding regulation of mRNA levels in response to changes in growth rate is encoded in the ORF and not in the promoter. Thus the ORF sequence is a major regulator of gene expression, and a non-linear interaction between promoters and ORFs determines mRNA levels.

systems biology↗

bioRxiv2017

Interaction Between Host MicroRNAs and the Gut Microbiota in Colorectal Cancer

BackgroundAlthough variation in gut microbiome composition has been linked with colorectal cancer (CRC), the factors that mediate the interactions between CRC tumors and the microbiome are poorly understood. MicroRNAs (miRNAs) are known to regulate CRC progression and patient survival outcomes. In addition, recent studies suggested that host miRNAs can also regulate bacterial growth and influence the composition of the gut microbiome. Here, we investigated the association between miRNAs expression in human CRC tumor and normal tissues and the microbiome composition associated with these same tissues.\n\nMethodWe sequenced the small RNAs from patient-matched tumor and normal tissue samples collected from 44 human CRC patients performed an integrated analysis with microbiome taxonomic composition data from these same samples. We then interrogated the functions of the bacteria correlated with miRNAs that were differentially expressed (DE) between tumor and matched normal tissues, as well as the functions of miRNAs correlated with bacterial taxa that have been previously associated with CRC, including Fusobacterium, Providencia, Bacteroides, Akkermansia, Roseburia, Porphyromonas, and Peptostreptococcus.\n\nResultsWe identified 76 miRNAs as DE between CRC and normal tissue, including known oncogenic miRNAs miR-182, miR-503, and miR-17[~]92. These DE miRNAs were correlated with the relative abundance of several bacterial taxa, including Firmicutes, Bacteroidetes, and Proteobacteria. Bacteria correlated with DE miRNAs were enriched with distinct predicted metabolic categories. Additionally, we found that miRNAs correlated with CRC-associated bacteria are predicted to regulate targets that are relevant for host-microbiome interactions, and highlight a possible role for miRNA-driven glycan production in the recruitment of pathogenic microbial taxa.\n\nConclusionsOur work characterized a global relationship between microbial community composition and miRNA expression in human CRC tissues. Our results support a role for miRNAs in mediating a bi-directional host-microbiome interaction in CRC. In addition, we highlight sets of potentially interacting microbes and host miRNAs, suggesting several pathways that can be targeted via future therapies.

systems biology↗

bioRxiv2017

Reprogramming, oscillations and transdifferentiation in epigenetic landscapes

Waddingtons epigenetic landscape provides a phenomenological understanding of the cell differentiation pathways from the pluripotent to mature lineage-committed cell lines. In light of recent successes in the reverse programming process there has been significant interest in quantifying the underlying landscape picture through the mathematics of gene regulatory networks. We investigate the role of time delays arising from multistep chemical reactions and epigenetic rearrangement on the cell differentiation landscape for a realistic two-gene regulatory network, consisting of selfpromoting and mutually inhibiting genes. Our work provides the first theoretical basis of the transdifferentiation process in the presence of delays, where one differentiated cell type can transition to another directly without passing through the undifferentiated state. Additionally, the interplay of time-delayed feedback and a time dependent chemical drive leads to long-lived oscillatory states in appropriate parameter regimes. This work emphasizes the important role played by time-delayed feedback loops in gene regulatory circuits and provides a framework for the characterization of epigenetic landscapes.

systems biology↗

bioRxiv2017

Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria

The pathogenesis of severe Plasmodium falciparum malaria is incompletely understood. Since the pathogenic stage of the parasite is restricted to blood, dual RNA-sequencing of host and parasite transcripts in blood can reveal their interactions at a systemic scale. Here we identify human and parasite gene expression associated with severe disease features in Gambian children. Differences in parasite load explained up to 99% of differential expression of human genes but only a third of the differential expression of parasite genes. Co-expression analyses showed a remarkable co-regulation of host and parasite genes controlling translation, and host granulopoiesis genes uniquely co-regulated and differentially expressed in severe malaria. Our results indicate that high parasite load is the proximal stimulus for severe P. falciparum malaria, that there is an unappreciated role for many parasite genes in determining virulence, and hint at a molecular arms-race between host and parasite to synthesise protein products.

systems biology↗

bioRxiv2017

Impact of spatial organization on a novel auxotrophic interaction among soil microbes

A key prerequisite to achieve a deeper understanding of microbial communities and to engineer synthetic ones is to identify the individual metabolic interactions among key species and how these interactions are affected by different environmental factors. Deciphering the physiological basis of species-species and species-environment interactions in spatially organized environment requires reductionist approaches using ecologically and functionally relevant species. To this end, we focus here on a specific defined system to study the metabolic interactions in a spatial context among a plant-beneficial endophytic fungus Serendipita indica, and the soil-dwelling model bacterium Bacillus subtilis. Focusing on the growth dynamics of S. indica under defined conditions, we identified an auxotrophy in this organism for thiamine, which is a key co-factor for essential reactions in the central carbon metabolism. We found that S. indica growth is restored in thiamine-free media, when co-cultured with B. subtilis. The success of this auxotrophic interaction, however, was dependent on the spatial and temporal organization of the system; the beneficial impact of B. subtilis was only visible when its inoculation was separated from that of S. indica either in time or space. These findings describe a key auxotrophic interaction in the soil among organisms that are shown to be important for plant ecosystem functioning, and point to the potential importance of spatial and temporal organization for the success of auxotrophic interactions. These points can be particularly important for engineering of minimal functional synthetic communities as plant-seed treatments and for vertical farming under defined conditions.

systems biology↗

bioRxiv2017

Discovery of global regulators of 3’ untranslated region processing in cancers with KAPAC

3 UTR length is regulated in relation to cellular state. To uncover key regulators of poly(A) site (PAS) use in specific conditions, we have developed PAQR, a method for quantifying PAS use from RNA sequencing data and KAPAC, an approach that infers activities of oligomeric sequence motifs on PAS choice. Application of PAQR and KAPAC to RNA sequencing data from normal and tumor tissue samples uncovered sequence motifs that can explain changes in cleavage and polyadenylation in specific cancers. In particular, our analysis points to Polypyrimidine tract binding protein 1 as a regulator of PAS choice in glioblastoma.

systems biology↗

bioRxiv2017

Timing of gene expression in a cell-fate decision system

During development, morphogens provide extracellular cues allowing cells to select a specific fate by inducing complex transcriptional programs. The mating pathway in budding yeast offers simplified settings to understand this process. Pheromone secreted by the mating partner triggers the activity of a MAPK pathway, which results in the expression of hundreds of genes. Using a dynamic expression reporter, we quantified the kinetics of gene expression in single cells upon exogenous pheromone stimulation and in the physiological context of mating. In both conditions, we observed striking differences in the timing of induction of mating-responsive promoters. Biochemical analyses and generation of synthetic promoter variants demonstrated how the interplay between transcription factor binding and nucleosomes contribute to determine the kinetics of transcription in a simplified cell-fate decision system.\n\nOne Sentence SummaryQuantitative and dynamic single cell measurements in the yeast mating pathway uncover a complex temporal orchestration of gene expression events.

systems biology↗

bioRxiv2017

Hierarchical organization endows the kinase domain with regulatory plasticity

The functional diversity of kinases enables specificity in cellular signal transduction. Yet general rules for how the kinase domain allows the more than 500 members of the human kinome to receive specific regulatory inputs and convey information to appropriate substrates - all while using the common signaling currency of phosphorylation - remain enigmatic. Here, using co-evolution analysis and quantitative live-cell assays, we reveal a deep hierarchical organization of the kinase domain that facilitates the orthogonal evolution of regulatory inputs and substrate outputs while maintaining catalytic function. Three quasi-independent functional units in the kinase domain (known as protein sectors) encode for catalysis, substrate specificity and regulation, and these distinct subdomains are differentially exploited by somatic cancer mutations and harnessed by allosteric inhibitors. We propose that this functional architecture endows the kinase domain with inherent regulatory plasticity.

systems biology↗

bioRxiv2017

Revisiting the erythroid-myeloid lineage decision - a data-driven dynamical model analysis

It is widely conjectured that the mutually antagonizing pair of transcription factors GATA1 and PU.1, deter-mines the choice between the erythroid and myeloid lineages in hematopoiesis. In theoretical approaches, this appears natural with a bistable switch driving the decision. Recent extensive binding and gene expression experiments with some focus on the triad GATA1, GATA2 and PU.1 indicate that GATA2 may be more involved in this lineage decision than previously anticipated. Here, we analyze these experimental data by modeling regulatory sub-networks with deterministic rate equations. Using network dynamical parameters determined by the data, we deduce from increasing the self-interaction bindings in silico among the triad genes that GATA2 and PU.1 exhibit non-linear behavior with one unstable and one stable state. This is in contrast to GATA1, which shows smoother behavior. We extend the network to include the downstream regulators FOG1 and CEBPA, and extract the nature of the corresponding regulatory interactions, excitatory or suppressing, between this pair and the triad by fitting to experimental gene expression time series. Based on this extended network, we simulate and explore different knockout scenarios, providing insight into the role of these regulators in the process of lineage specification, as well as predictions for future experimental validation. We address the mechanism of GATA switching as a mechanism of lineage differentiation by investigating the dynamics of FOG1 regulation by GATA2 and GATA1. Overall, this analysis strongly suggests that within this network, GATA2 is the key driver of erythroid lineage specification through its repression of PU.1, whereas GATA1 appears to be more relevant for the downstream differentiation events.

systems biology↗

bioRxiv2017

Evolution-informed forecasting of seasonal influenza A (H3N2)

Inter-pandemic or seasonal influenza exacts an enormous annual burden both in terms of human health and economic impact. Incidence prediction ahead of season remains a challenge largely because of the virus antigenic evolution. We propose here a forecasting approach that incorporates evolutionary change into a mechanistic epidemiological model. The proposed models are simple enough that their parameters can be estimated from retrospective surveillance data. These models link amino-acid sequences of hemagglutinin epitopes with a transmission model for seasonal H3N2 influenza, also informed by H1N1 levels. With a monthly time series of H3N2 incidence in the United States over 10 years, we demonstrate the feasibility of prediction ahead of season and an accurate real-time forecast for the 2016/2017 influenza season.\n\nSUMMARYSkillful forecasting of seasonal (H3N2) influenza incidence ahead of the season is shown to be possible by means of a transmission model that explicitly tracks evolutionary change in the virus, integrating information from both epidemiological surveillance and readily available genetic sequences.

systems biology↗

bioRxiv2017

Predicting microRNA targeting efficacy in Drosophila

Important for understanding the regulatory roles of miRNAs is the ability to predict the mRNA targets most responsive to each miRNA. Here, we acquired datasets needed for the quantitative study of microRNA targeting in Drosophila. Analyses of these data expanded the types of sites known to be effective in flies, expanded the mRNA regions with detectable targeting to include 5' UTRs, and identified features of site context that correlate with targeting efficacy. Updated evolutionary analyses evaluated the probability of conserved targeting for each predicted site and indicated that more than a third of the Drosophila genes are preferentially conserved targets of miRNAs. Based on these results, a quantitative model was developed to predict targeting efficacy in insects. This model performed better than existing models and will drive the next version of TargetScanFly (v7.0; targetscan.org), thereby providing a valuable resource for placing miRNAs into gene-regulatory networks of this important experimental organism.

systems biology↗