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Molecular Systems Biology

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https://www.readbyqxmd.com/read/28202506/recurrent-patterns-of-dna-copy-number-alterations-in-tumors-reflect-metabolic-selection-pressures
#1
Nicholas A Graham, Aspram Minasyan, Anastasia Lomova, Ashley Cass, Nikolas G Balanis, Michael Friedman, Shawna Chan, Sophie Zhao, Adrian Delgado, James Go, Lillie Beck, Christian Hurtz, Carina Ng, Rong Qiao, Johanna Ten Hoeve, Nicolaos Palaskas, Hong Wu, Markus Müschen, Asha S Multani, Elisa Port, Steven M Larson, Nikolaus Schultz, Daniel Braas, Heather R Christofk, Ingo K Mellinghoff, Thomas G Graeber
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including (18)F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation...
February 15, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28193641/a-method-for-high-throughput-production-of-sequence-verified-dna-libraries-and-strain-collections
#2
Justin D Smith, Ulrich Schlecht, Weihong Xu, Sundari Suresh, Joe Horecka, Michael J Proctor, Raeka S Aiyar, Richard A O Bennett, Angela Chu, Yong Fuga Li, Kevin Roy, Ronald W Davis, Lars M Steinmetz, Richard W Hyman, Sasha F Levy, Robert P St Onge
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...
February 13, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28183842/metabolic-pattern-formation-in-the-tumor%C3%A2-microenvironment
#3
Ziwei Dai, Jason W Locasale
No abstract text is available yet for this article.
February 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28183841/mathematical-modeling-links-wnt-signaling-to-emergent-patterns-of-metabolism-in-colon-cancer
#4
Mary Lee, George T Chen, Eric Puttock, Kehui Wang, Robert A Edwards, Marian L Waterman, John Lowengrub
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...
February 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28167566/transcription-factor-family-specific-dna-shape-readout-revealed-by-quantitative-specificity-models
#5
Lin Yang, Yaron Orenstein, Arttu Jolma, Yimeng Yin, Jussi Taipale, Ron Shamir, Remo Rohs
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 in core motif-flanking regions...
February 6, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28137776/combinatorial-actions-of-bacterial-effectors-revealed-by-exploiting-genetic-tools-in-yeast
#6
Alan Huett
No abstract text is available yet for this article.
January 30, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28137775/a-living-vector-field-reveals-constraints-on-galactose-network-induction-in-yeast
#7
Sarah R Stockwell, Scott A Rifkin
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 switched to galactose from various nutrient histories...
January 30, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28123004/protein-abundance-of-akt-and-erk-pathway-components-governs-cell-type-specific-regulation-of%C3%A2-proliferation
#8
Lorenz Adlung, Sandip Kar, Marie-Christine Wagner, Bin She, Sajib Chakraborty, Jie Bao, Susen Lattermann, Melanie Boerries, Hauke Busch, Patrick Wuchter, Anthony D Ho, Jens Timmer, Marcel Schilling, Thomas Höfer, Ursula Klingmüller
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...
January 24, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28115550/stochastic-gene-expression-bacterial-elites-in-chemotaxis
#9
Simon van Vliet, Martin Ackermann
No abstract text is available yet for this article.
January 23, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28093455/genomewide-landscape-of-gene-metabolome-associations-in-escherichia-coli
#10
Tobias Fuhrer, Mattia Zampieri, Daniel C Sévin, Uwe Sauer, Nicola Zamboni
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...
January 16, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28082348/interactome-disassembly-during-apoptosis-occurs-independent-of-caspase-cleavage
#11
Nichollas E Scott, Lindsay D Rogers, Anna Prudova, Nat F Brown, Nikolaus Fortelny, Christopher M Overall, Leonard J Foster
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...
January 12, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28069687/adaptive-resistance-of-melanoma-cells-to-raf-inhibition-via-reversible-induction-of-a-slowly-dividing-de-differentiated-state
#12
Mohammad Fallahi-Sichani, Verena Becker, Benjamin Izar, Gregory J Baker, Jia-Ren Lin, Sarah A Boswell, Parin Shah, Asaf Rotem, Levi A Garraway, Peter K Sorger
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...
January 9, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28049137/few-regulatory-metabolites-coordinate-expression-of-central-metabolic-genes-in-escherichia-coli
#13
Karl Kochanowski, Luca Gerosa, Simon F Brunner, Dimitris Christodoulou, Yaroslav V Nikolaev, Uwe Sauer
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...
January 3, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28049136/early-commitment-and-robust-differentiation-in-colonic-crypts
#14
Beáta Tóth, Shani Ben-Moshe, Avishai Gavish, Naama Barkai, Shalev Itzkovitz
Tissue stem cells produce a constant flux of differentiated cells with distinct proportions. Here, we show that stem cells in colonic crypts differentiate early to form precisely 1:3 ratio of secretory to absorptive cells. This precision is surprising, as there are only eight stem cells making irreversible fate decisions, and so large stochastic effects of this small pool should have yielded much larger noise in cell proportions. We use single molecule FISH, lineage-tracing mice and simulations to identify the homeostatic mechanisms facilitating robust proportions...
January 3, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28043953/subgenic-pol-ii-interactomes-identify-region-specific-transcription-elongation-regulators
#15
Kevin M Harlen, L Stirling Churchman
Transcription, RNA processing, and chromatin-related factors all interact with RNA polymerase II (Pol II) to ensure proper timing and coordination of transcription and co-transcriptional processes. Many transcription elongation regulators must function simultaneously to coordinate these processes, yet few strategies exist to explore the complement of factors regulating specific stages of transcription. To this end, we developed a strategy to purify Pol II elongation complexes from subgenic regions of a single gene, namely the 5' and 3' regions, using sequences in the nascent RNA...
January 2, 2017: Molecular Systems Biology
https://www.readbyqxmd.com/read/28034910/yeast-gpcr-signaling-reflects-the-fraction-of-occupied-receptors-not-the-number
#16
Alan Bush, Gustavo Vasen, Andreas Constantinou, Paula Dunayevich, Inés Lucía Patop, Matías Blaustein, Alejandro Colman-Lerner
According to receptor theory, the effect of a ligand depends on the amount of agonist-receptor complex. Therefore, changes in receptor abundance should have quantitative effects. However, the response to pheromone in Saccharomyces cerevisiae is robust (unaltered) to increases or reductions in the abundance of the G-protein-coupled receptor (GPCR), Ste2, responding instead to the fraction of occupied receptor. We found experimentally that this robustness originates during G-protein activation. We developed a complete mathematical model of this step, which suggested the ability to compute fractional occupancy depends on the physical interaction between the inhibitory regulator of G-protein signaling (RGS), Sst2, and the receptor...
December 29, 2016: Molecular Systems Biology
https://www.readbyqxmd.com/read/28031353/model-guided-combinatorial-optimization-of-complex-synthetic-gene-networks
#17
Joerg Schreiber, Meret Arter, Nicolas Lapique, Benjamin Haefliger, Yaakov Benenson
Constructing gene circuits that satisfy quantitative performance criteria has been a long-standing challenge in synthetic biology. Here, we show a strategy for optimizing a complex three-gene circuit, a novel proportional miRNA biosensor, using predictive modeling to initiate a search in the phase space of sensor genetic composition. We generate a library of sensor circuits using diverse genetic building blocks in order to access favorable parameter combinations and uncover specific genetic compositions with greatly improved dynamic range...
December 28, 2016: Molecular Systems Biology
https://www.readbyqxmd.com/read/28007936/proteomics-reveals-the-effects-of-sustained-weight-loss-on-the-human-plasma-proteome
#18
Philipp E Geyer, Nicolai J Wewer Albrechtsen, Stefka Tyanova, Niklas Grassl, Eva W Iepsen, Julie Lundgren, Sten Madsbad, Jens J Holst, Signe S Torekov, Matthias Mann
Sustained weight loss is a preferred intervention in a wide range of metabolic conditions, but the effects on an individual's health state remain ill-defined. Here, we investigate the plasma proteomes of a cohort of 43 obese individuals that had undergone 8 weeks of 12% body weight loss followed by a year of weight maintenance. Using mass spectrometry-based plasma proteome profiling, we measured 1,294 plasma proteomes. Longitudinal monitoring of the cohort revealed individual-specific protein levels with wide-ranging effects of losing weight on the plasma proteome reflected in 93 significantly affected proteins...
December 22, 2016: Molecular Systems Biology
https://www.readbyqxmd.com/read/28007935/frequency-doubling-in-the-cyanobacterial-circadian-clock
#19
Bruno Mc Martins, Arijit K Das, Liliana Antunes, James Cw Locke
Organisms use circadian clocks to generate 24-h rhythms in gene expression. However, the clock can interact with other pathways to generate shorter period oscillations. It remains unclear how these different frequencies are generated. Here, we examine this problem by studying the coupling of the clock to the alternative sigma factor sigC in the cyanobacterium Synechococcus elongatus Using single-cell microscopy, we find that psbAI, a key photosynthesis gene regulated by both sigC and the clock, is activated with two peaks of gene expression every circadian cycle under constant low light...
December 22, 2016: Molecular Systems Biology
https://www.readbyqxmd.com/read/27994041/non-genetic-diversity-modulates-population-performance
#20
Adam James Waite, Nicholas W Frankel, Yann S Dufour, Jessica F Johnston, Junjiajia Long, Thierry Emonet
Biological functions are typically performed by groups of cells that express predominantly the same genes, yet display a continuum of phenotypes. While it is known how one genotype can generate such non-genetic diversity, it remains unclear how different phenotypes contribute to the performance of biological function at the population level. We developed a microfluidic device to simultaneously measure the phenotype and chemotactic performance of tens of thousands of individual, freely swimming Escherichia coli as they climbed a gradient of attractant...
December 19, 2016: Molecular Systems Biology
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