Transfer of dysbiotic gut microbiota has beneficial effects on host liver metabolism
Gut microbiota dysbiosis has been implicated in a variety of systemic disorders, notably metabolic diseases including obesity and impaired liver function, but the underlying mechanisms are uncertain. To investigate this question, we transferred caecal microbiota from either obese or lean mice to antibiotic-free, conventional wild-type mice. We found that transferring obese-mouse gut microbiota to mice on normal chow (NC) acutely reduces markers of hepatic gluconeogenesis with decreased hepatic PEPCK activity, compared to non-inoculated mice, a phenotypic trait blunted in conventional NOD2 KO mice. Furthermore, transferring...
Source: Molecular Systems Biology - March 15, 2017 Category: Molecular Biology Authors: Nicolas, S., Blasco-Baque, V., Fournel, A., Gilleron, J., Klopp, P., Waget, A., Ceppo, F., Marlin, A., Padmanabhan, R., Iacovoni, J. S., Terce, F., Cani, P. D., Tanti, J.-F., Burcelin, R., Knauf, C., Cormont, M., Serino, M. Tags: Genome-Scale & Integrative Biology, Metabolism, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
TT-seq captures enhancer landscapes immediately after T-cell stimulation
To monitor transcriptional regulation in human cells, rapid changes in enhancer and promoter activity must be captured with high sensitivity and temporal resolution. Here, we show that the recently established protocol TT-seq ("transient transcriptome sequencing") can monitor rapid changes in transcription from enhancers and promoters during the immediate response of T cells to ionomycin and phorbol 12-myristate 13-acetate (PMA). TT-seq maps eRNAs and mRNAs every 5 min after T-cell stimulation with high sensitivity and identifies many new primary response genes. TT-seq reveals that the synthesis of 1,601 eRNAs and 650...
Source: Molecular Systems Biology - March 6, 2017 Category: Molecular Biology Authors: Michel, M., Demel, C., Zacher, B., Schwalb, B., Krebs, S., Blum, H., Gagneur, J., Cramer, P. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Transcription Articles Source Type: research
Metabolic constraints on the evolution of antibiotic resistance
Despite our continuous improvement in understanding antibiotic resistance, the interplay between natural selection of resistance mutations and the environment remains unclear. To investigate the role of bacterial metabolism in constraining the evolution of antibiotic resistance, we evolved Escherichia coli growing on glycolytic or gluconeogenic carbon sources to the selective pressure of three different antibiotics. Profiling more than 500 intracellular and extracellular putative metabolites in 190 evolved populations revealed that carbon and energy metabolism strongly constrained the evolutionary trajectories, both in ter...
Source: Molecular Systems Biology - March 5, 2017 Category: Molecular Biology Authors: Zampieri, M., Enke, T., Chubukov, V., Ricci, V., Piddock, L., Sauer, U. Tags: Genome-Scale & Integrative Biology, Metabolism, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
A method for high-throughput production of sequence-verified DNA libraries and strain collections
The low costs of array-synthesized oligonucleotide libraries are empowering rapid advances in quantitative and synthetic biology. However, high synthesis error rates, uneven representation, and lack of access to individual oligonucleotides limit the true potential of these libraries. We have developed a cost-effective method called Recombinase Directed Indexing (REDI), which involves integration of a complex library into yeast, site-specific recombination to index library DNA, and next-generation sequencing to identify desired clones. We used REDI to generate a library of ~3,300 DNA probes that exhibited > 96% puri...
Source: Molecular Systems Biology - February 12, 2017 Category: Molecular Biology Authors: Smith, J. D., Schlecht, U., Xu, W., Suresh, S., Horecka, J., Proctor, M. J., Aiyar, R. S., Bennett, R. A. O., Chu, A., Li, Y. F., Roy, K., Davis, R. W., Steinmetz, L. M., Hyman, R. W., Levy, S. F., St.Onge, R. P. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Methods & Resources Articles Source Type: research
Metabolic pattern formation in the tumor microenvironment
Metabolic alterations including increased glycolysis are a common feature of many cancers. In their recent study, Lowengrub, Waterman, and colleagues (Lee et al, 2017) report a spatial pattern of glycolysis in solid tumors that occurs within the tumor microenvironment. This spatial organization is linked to gradients derived from Wnt signaling and nutrient availability that mediate a reaction-diffusion mechanism and is consistent with a Turing-type model of spatial localization. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - February 8, 2017 Category: Molecular Biology Authors: Dai, Z., Locasale, J. W. Tags: Cancer, Quantitative Biology & Dynamical Systems, Signal Transduction News [amp ] Views Source Type: research
Mathematical modeling links Wnt signaling to emergent patterns of metabolism in colon cancer
Cell-intrinsic metabolic reprogramming is a hallmark of cancer that provides anabolic support to cell proliferation. How reprogramming influences tumor heterogeneity or drug sensitivities is not well understood. Here, we report a self-organizing spatial pattern of glycolysis in xenograft colon tumors where pyruvate dehydrogenase kinase (PDK1), a negative regulator of oxidative phosphorylation, is highly active in clusters of cells arranged in a spotted array. To understand this pattern, we developed a reaction–diffusion model that incorporates Wnt signaling, a pathway known to upregulate PDK1 and Warburg metabolism. ...
Source: Molecular Systems Biology - February 8, 2017 Category: Molecular Biology Authors: Lee, M., Chen, G. T., Puttock, E., Wang, K., Edwards, R. A., Waterman, M. L., Lowengrub, J. Tags: Cancer, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Transcription factor family-specific DNA shape readout revealed by quantitative specificity models
Transcription factors (TFs) achieve DNA-binding specificity through contacts with functional groups of bases (base readout) and readout of structural properties of the double helix (shape readout). Currently, it remains unclear whether DNA shape readout is utilized by only a few selected TF families, or whether this mechanism is used extensively by most TF families. We resequenced data from previously published HT-SELEX experiments, the most extensive mammalian TF–DNA binding data available to date. Using these data, we demonstrated the contributions of DNA shape readout across diverse TF families and its importance ...
Source: Molecular Systems Biology - February 5, 2017 Category: Molecular Biology Authors: Yang, L., Orenstein, Y., Jolma, A., Yin, Y., Taipale, J., Shamir, R., Rohs, R. Tags: Genome-Scale & Integrative Biology, Structural Biology, Transcription Articles Source Type: research
A living vector field reveals constraints on galactose network induction in yeast
When a cell encounters a new environment, its transcriptional response can be constrained by its history. For example, yeast cells in galactose induce GAL genes with a speed and unanimity that depends on previous nutrient conditions. Cellular memory of long-term glucose exposure delays GAL induction and makes it highly variable with in a cell population, while other nutrient histories lead to rapid, uniform responses. To investigate how cell-level gene expression dynamics produce population-level phenotypes, we built living vector fields from thousands of single-cell time courses of the proteins Gal3p and Gal1p as cells sw...
Source: Molecular Systems Biology - January 29, 2017 Category: Molecular Biology Authors: Stockwell, S. R., Rifkin, S. A. Tags: Quantitative Biology & Dynamical Systems, Transcription Articles Source Type: research
Combinatorial actions of bacterial effectors revealed by exploiting genetic tools in yeast
While yeast has been extensively used as a model system for analysing protein–protein and genetic interactions, in the context of bacterial pathogenesis, the use of yeast-based tools has largely been limited to identifying interactions between pathogen effectors and host targets. In their recent work, Ensminger and colleagues (Urbanus et al, 2016) use the combinatorial power of yeast genetics to systematically screen all known Legionella pneumophila effector proteins for effector–effector interactions. They provide new insights into how bacterial effectors balance host cell perturbation and describe m...
Source: Molecular Systems Biology - January 29, 2017 Category: Molecular Biology Authors: Huett, A. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genetics, Gene Therapy & Genetic Disease, Microbiology, Virology & Host Pathogen Interaction News [amp ] Views Source Type: research
Protein abundance of AKT and ERK pathway components governs cell type-specific regulation of proliferation
Signaling through the AKT and ERK pathways controls cell proliferation. However, the integrated regulation of this multistep process, involving signal processing, cell growth and cell cycle progression, is poorly understood. Here, we study different hematopoietic cell types, in which AKT and ERK signaling is triggered by erythropoietin (Epo). Although these cell types share the molecular network topology for pro-proliferative Epo signaling, they exhibit distinct proliferative responses. Iterating quantitative experiments and mathematical modeling, we identify two molecular sources for cell type-specific proliferation. Firs...
Source: Molecular Systems Biology - January 23, 2017 Category: Molecular Biology Authors: Adlung, L., Kar, S., Wagner, M.-C., She, B., Chakraborty, S., Bao, J., Lattermann, S., Boerries, M., Busch, H., Wuchter, P., Ho, A. D., Timmer, J., Schilling, M., Höfer, T., Klingmüller, U. Tags: Cell Cycle, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Stochastic gene expression: bacterial elites in chemotaxis
Even in the absence of genetic or environmental differences, cells differ from each other in their molecular make-up. The consequences of these phenotypic differences are often not well understood. New work by Waite et al (2016) directly links variation in the molecular composition of individual bacterial cells to their population-level performance. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - January 22, 2017 Category: Molecular Biology Authors: van Vliet, S., Ackermann, M. Tags: Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems, Signal Transduction News [amp ] Views Source Type: research
Genomewide landscape of gene-metabolome associations in Escherichia coli
Metabolism is one of the best-understood cellular processes whose network topology of enzymatic reactions is determined by an organism's genome. The influence of genes on metabolite levels, however, remains largely unknown, particularly for the many genes encoding non-enzymatic proteins. Serendipitously, genomewide association studies explore the relationship between genetic variants and metabolite levels, but a comprehensive interaction network has remained elusive even for the simplest single-celled organisms. Here, we systematically mapped the association between > 3,800 single-gene deletions in the bacterium Es...
Source: Molecular Systems Biology - January 15, 2017 Category: Molecular Biology Authors: Fuhrer, T., Zampieri, M., Sevin, D. C., Sauer, U., Zamboni, N. Tags: Genome-Scale & Integrative Biology, Metabolism, Methods & Resources Articles Source Type: research
Interactome disassembly during apoptosis occurs independent of caspase cleavage
Protein–protein interaction networks (interactomes) define the functionality of all biological systems. In apoptosis, proteolysis by caspases is thought to initiate disassembly of protein complexes and cell death. Here we used a quantitative proteomics approach, protein correlation profiling (PCP), to explore changes in cytoplasmic and mitochondrial interactomes in response to apoptosis initiation as a function of caspase activity. We measured the response to initiation of Fas-mediated apoptosis in 17,991 interactions among 2,779 proteins, comprising the largest dynamic interactome to date. The majority of interactio...
Source: Molecular Systems Biology - January 11, 2017 Category: Molecular Biology Authors: Scott, N. E., Rogers, L. D., Prudova, A., Brown, N. F., Fortelny, N., Overall, C. M., Foster, L. J. Tags: Autophagy & Cell Death, Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state
Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly. This phenotype is transiently stable, reverting to the drug-naïve ...
Source: Molecular Systems Biology - January 8, 2017 Category: Molecular Biology Authors: Fallahi-Sichani, M., Becker, V., Izar, B., Baker, G. J., Lin, J.-R., Boswell, S. A., Shah, P., Rotem, A., Garraway, L. A., Sorger, P. K. Tags: Molecular Biology of Disease, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Few regulatory metabolites coordinate expression of central metabolic genes in Escherichia coli
Transcription networks consist of hundreds of transcription factors with thousands of often overlapping target genes. While we can reliably measure gene expression changes, we still understand relatively little why expression changes the way it does. How does a coordinated response emerge in such complex networks and how many input signals are necessary to achieve it? Here, we unravel the regulatory program of gene expression in Escherichia coli central carbon metabolism with more than 30 known transcription factors. Using a library of fluorescent transcriptional reporters, we comprehensively quantify the activity of centr...
Source: Molecular Systems Biology - January 2, 2017 Category: Molecular Biology Authors: Kochanowski, K., Gerosa, L., Brunner, S. F., Christodoulou, D., Nikolaev, Y. V., Sauer, U. Tags: Genome-Scale & Integrative Biology, Metabolism, Transcription Articles Source Type: research
