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  • Apoptosis and other immune biomarkers predict influenza vaccine responsiveness
    David Furman, Vladimir Jojic, Brian Kidd, Shai Shen‐Orr, Jordan Price, Justin Jarrell, Tiffany Tse, Huang Huang, Peder Lund, Holden T Maecker, Paul J Utz, Cornelia L Dekker, Daphne Koller, Mark M Davis
  • Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers
    Jüri Reimand, Gary D Bader
  • Quantitative analysis of mammalian translation initiation sites by FACS‐seq
    1. William L Noderer1,
    2. Ross J Flockhart2,
    3. Aparna Bhaduri2,3,
    4. Alexander J Diaz de Arce1,
    5. Jiajing Zhang2,
    6. Paul A Khavari2,4 and
    7. Clifford L Wang*,1
    1. 1Department of Chemical Engineering, Stanford University, Stanford, CA, USA
    2. 2The Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA
    3. 3The Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA, USA
    4. 4Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA, USA
    1. *Corresponding author. Tel: +1 650 736 1807; Fax: +1 650 725 7294; E‐mail: cliff.wang{at}stanford.edu

    The impact of the translation initiation site (TIS) sequence on translational efficiency is determined by FACS‐seq, combining cell sorting and high‐throughput sequencing. A quantitative model of initiation links TIS mutations with tumorigenesis and predicts translational protein isoforms.

    Synopsis

    The impact of the translation initiation site (TIS) sequence on translational efficiency is determined by FACS‐seq, combining cell sorting and high‐throughput sequencing. A quantitative model of initiation links TIS mutations with tumorigenesis and predicts translational protein isoforms.

    • Translation efficiency is analyzed for all possible TIS sequences utilizing an AUG start codon and an RYMRMVAUGGC motif is found to be optimal for translation initiation.

    • Dinucleotide interactions, which cannot be conveyed in a single motif, influence initiation efficiency.

    • TIS mutations affect protein expression similarly to known tumor expression patterns, thereby putatively linking the mutations and tumor formation.

    • Leaky scanning results in N‐terminal truncated protein isoforms and enhances proteome diversity.

    • FACS‐seq
    • Kozak motif
    • proteome modeling
    • start codon
    • translation initiation

    Mol Syst Biol. (2014) 10: 748

    • Received January 17, 2014.
    • Revision received July 22, 2014.
    • Accepted July 24, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    William L Noderer, Ross J Flockhart, Aparna Bhaduri, Alexander J Diaz de Arce, Jiajing Zhang, Paul A Khavari, Clifford L Wang
  • Emergence of robust growth laws from optimal regulation of ribosome synthesis
    1. Matthew Scott*,1,
    2. Stefan Klumpp2,
    3. Eduard M Mateescu3 and
    4. Terence Hwa3,4
    1. 1Department of Applied Mathematics, University of Waterloo, Waterloo, ON, Canada
    2. 2Max Planck Institute of Colloids and Interfaces, Potsdam, Germany
    3. 3Department of Physics and Center for Theoretical Biological Physics, University of California, San Diego La Jolla, CA, USA
    4. 4Institute for Theoretical Studies, ETH Zurich, Zurich, Switzerland
    1. *Corresponding author. Tel: +1 519 888 4567 ext. 35454; E‐mail: mscott{at}math.uwaterloo.ca

    Building upon empirical “growth laws”, this Perspective discusses mechanisms that integrate protein synthesis with amino acid flux and metabolic control to guarantee optimal growth irrespective of the nutrient environment.

    • growth control
    • metabolic control
    • phenomenological model
    • resource allocation
    • synthetic biology

    Mol Syst Biol. (2014) 10: 747

    • Received April 20, 2014.
    • Revision received July 11, 2014.
    • Accepted July 14, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Matthew Scott, Stefan Klumpp, Eduard M Mateescu, Terence Hwa
  • Specificity, propagation, and memory of pericentric heterochromatin
    1. Katharina Müller‐Ott1,
    2. Fabian Erdel1,
    3. Anna Matveeva2,
    4. Jan‐Philipp Mallm1,
    5. Anne Rademacher1,
    6. Matthias Hahn3,
    7. Caroline Bauer1,
    8. Qin Zhang2,
    9. Sabine Kaltofen14,
    10. Gunnar Schotta3,
    11. Thomas Höfer2 and
    12. Karsten Rippe*,1
    1. 1Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Research Group Genome Organization & Function, Heidelberg, Germany
    2. 2Deutsches Krebsforschungszentrum (DKFZ) and BioQuant, Division Theoretical Systems Biology, Heidelberg, Germany
    3. 3Munich Center for Integrated Protein Science and Adolf Butenandt Institute, Ludwig Maximilians University, Munich, Germany
    4. 4 Biochemistry & Structural Biology, Lund University, Lund, Sweden
    1. *Corresponding author. Tel: +49 6221 5451376; Fax: +49 6221 5451487; E‐mail: karsten.rippe{at}dkfz.de

    A comprehensive analysis of the epigenetic network that silences pericentric heterochromatin (PCH) transcription in mouse fibroblasts is presented. The resulting quantitative model explains the spatial extension, stability and propagation of histone modification domains.

    Synopsis

    A comprehensive analysis of the epigenetic network that silences pericentric heterochromatin (PCH) transcription in mouse fibroblasts is presented. The resulting quantitative model explains the spatial extension, stability and propagation of histone modification domains.

    • A quantitative map of the abundance and interactions of 16 PCH factors is generated by fluorescence microscopy/spectroscopy and ChIP‐seq.

    • A predictive mathematical model, based on the quantitative data, explains how the silenced PCH state is maintained and transmitted through the cell cycle.

    • A “nucleation and looping” mechanism is proposed, in which chromatin‐bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated H3K9me3 modifications via chromatin dynamics.

    • FRAP/FCS
    • heterochromatin protein 1
    • histone methylation
    • pericentric heterochromatin
    • protein network

    Mol Syst Biol. (2014) 10: 746

    • Received April 19, 2014.
    • Revision received July 10, 2014.
    • Accepted July 15, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Katharina Müller‐Ott, Fabian Erdel, Anna Matveeva, Jan‐Philipp Mallm, Anne Rademacher, Matthias Hahn, Caroline Bauer, Qin Zhang, Sabine Kaltofen, Gunnar Schotta, Thomas Höfer, Karsten Rippe
  • A computational study of the Warburg effect identifies metabolic targets inhibiting cancer migration
    1. Keren Yizhak*,1,,
    2. Sylvia E Le Dévédec2,,
    3. Vasiliki Maria Rogkoti2,
    4. Franziska Baenke3,
    5. Vincent C de Boer4,
    6. Christian Frezza5,
    7. Almut Schulze3,
    8. Bob van de Water2, and
    9. Eytan Ruppin*,1,6,
    1. 1The Blavatnik School of Computer Science, Tel‐Aviv University, Tel‐Aviv, Israel
    2. 2Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
    3. 3Gene Expression Analysis Laboratory, Cancer Research UK, London Research Institute, London, UK
    4. 4Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
    5. 5MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Cambridge, UK
    6. 6The Sackler School of Medicine, Tel‐Aviv University, Tel‐Aviv, Israel
    1. * Corresponding author. Tel: +972 3 6405378; E‐mail: kerenyiz{at}post.tau.ac.il

      Corresponding author. Tel: +972 3 6406528; E‐mail: ruppin{at}post.tau.ac.il

    1. These authors contributed equally to this study

    2. These authors contributed equally to this study

    A computational analysis based on genome‐scale metabolic models shows that the extent of the Warburg effect is highly associated with cancer cell migration across different cell lines and identifies anti‐migratory targets.

    Synopsis

    A computational analysis based on genome‐scale metabolic models shows that the extent of the Warburg effect is highly associated with cancer cell migration across different cell lines and identifies anti‐migratory targets.

    • Genome‐scale metabolic models of each the NCI‐60 cell lines correctly capture the Warburg effect.

    • The extent of the Warburg effect, as quantified by the ratio between glycolytic and oxidative ATP flux rate (AFR), positively associates with cancer cell migration across the different cell lines.

    • siRNA knockdown of 13 genes predicted to reduce the AFR attenuates cell migration while having almost no effect on cell proliferation.

    • In agreement with the predictions, a significant reduction in the ratio of glycolytic/oxidative capacity is observed following these gene perturbations.

    • cancer cell migration
    • cellular metabolism
    • genome‐scale metabolic modeling

    Mol Syst Biol. (2014) 10: 744

    • Received November 18, 2013.
    • Revision received July 6, 2014.
    • Accepted July 7, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Keren Yizhak, Sylvia E Le Dévédec, Vasiliki Maria Rogkoti, Franziska Baenke, Vincent C de Boer, Christian Frezza, Almut Schulze, Bob van de Water, Eytan Ruppin
  • A ‘resource allocator’ for transcription based on a highly fragmented T7 RNA polymerase
    1. Thomas H Segall‐Shapiro1,
    2. Adam J Meyer2,
    3. Andrew D Ellington2,
    4. Eduardo D Sontag3 and
    5. Christopher A Voigt*,1
    1. 1Department of Biological Engineering, Synthetic Biology Center Massachusetts Institute of Technology, Cambridge, MA, USA
    2. 2Institute for Cellular and Molecular Biology University of Texas at Austin, Austin, TX, USA
    3. 3Department of Mathematics, Rutgers University, Piscataway, NJ, USA
    1. *Corresponding author. Tel: +1 617 324 4851; E‐mail: cavoigt{at}gmail.com

    The T7 RNA polymerase is split into two to four fragments that retain activity when co‐expressed. These parts provide a toolbox to allocate resources to a genetic system, set its transcriptional activity and partition it between multiple orthogonal promoters.

    Synopsis

    The T7 RNA polymerase is split into two to four fragments that retain activity when co‐expressed. These parts provide a toolbox to allocate resources to a genetic system, set its transcriptional activity and partition it between multiple orthogonal promoters.

    • T7 RNA polymerase is bisected at five distinct regions and combinations of these fragments yield active three‐ and four‐piece polymerases.

    • Specificity loop mutations introduced to the C‐terminal fragment, create variable “σ fragments” that bind to the remaining conserved “core fragment” and activate orthogonal promoters.

    • Using the σ and core fragments, a resource allocator is built that can regulate the total transcriptional activity of a synthetic system and dynamically partition it between promoters.

    • Further splits and mutations are used to build positive and negative regulators of the resource allocator, enabling more complex system architectures.

    • genetic circuit
    • resource allocation
    • split protein
    • synthetic biology
    • T7 RNA polymerase

    Mol Syst Biol. (2014) 10: 742

    • Received March 21, 2014.
    • Revision received June 5, 2014.
    • Accepted June 24, 2014.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Thomas H Segall‐Shapiro, Adam J Meyer, Andrew D Ellington, Eduardo D Sontag, Christopher A Voigt