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Molecular Systems Biology

Thomas E Gorochowski, Amin Espah Borujeni, Yongjin Park, Alec Ak Nielsen, Jing Zhang, Bryan S Der, D Benjamin Gordon, Christopher A Voigt
Genetic circuits implement computational operations within a cell. Debugging them is difficult because their function is defined by multiple states (e.g., combinations of inputs) that vary in time. Here, we develop RNA-seq methods that enable the simultaneous measurement of: (i) the states of internal gates, (ii) part performance (promoters, insulators, terminators), and (iii) impact on host gene expression. This is applied to a three-input one-output circuit consisting of three sensors, five NOR/NOT gates, and 46 genetic parts...
November 9, 2017: Molecular Systems Biology
Eunyong Ahn, Praveen Kumar, Dzmitry Mukha, Amit Tzur, Tomer Shlomi
Cellular metabolic demands change throughout the cell cycle. Nevertheless, a characterization of how metabolic fluxes adapt to the changing demands throughout the cell cycle is lacking. Here, we developed a temporal-fluxomics approach to derive a comprehensive and quantitative view of alterations in metabolic fluxes throughout the mammalian cell cycle. This is achieved by combining pulse-chase LC-MS-based isotope tracing in synchronized cell populations with computational deconvolution and metabolic flux modeling...
November 6, 2017: Molecular Systems Biology
Martin Frejno, Riccardo Zenezini Chiozzi, Mathias Wilhelm, Heiner Koch, Runsheng Zheng, Susan Klaeger, Benjamin Ruprecht, Chen Meng, Karl Kramer, Anna Jarzab, Stephanie Heinzlmeir, Elaine Johnstone, Enric Domingo, David Kerr, Moritz Jesinghaus, Julia Slotta-Huspenina, Wilko Weichert, Stefan Knapp, Stephan M Feller, Bernhard Kuster
Most molecular cancer therapies act on protein targets but data on the proteome status of patients and cellular models for proteome-guided pre-clinical drug sensitivity studies are only beginning to emerge. Here, we profiled the proteomes of 65 colorectal cancer (CRC) cell lines to a depth of > 10,000 proteins using mass spectrometry. Integration with proteomes of 90 CRC patients and matched transcriptomics data defined integrated CRC subtypes, highlighting cell lines representative of each tumour subtype...
November 3, 2017: Molecular Systems Biology
Alvaro Rada-Iglesias
No abstract text is available yet for this article.
October 23, 2017: Molecular Systems Biology
Markus Hartl, Magdalena Füßl, Paul J Boersema, Jan-Oliver Jost, Katharina Kramer, Ahmet Bakirbas, Julia Sindlinger, Magdalena Plöchinger, Dario Leister, Glen Uhrig, Greg Bg Moorhead, Jürgen Cox, Michael E Salvucci, Dirk Schwarzer, Matthias Mann, Iris Finkemeier
Histone deacetylases have central functions in regulating stress defenses and development in plants. However, the knowledge about the deacetylase functions is largely limited to histones, although these enzymes were found in diverse subcellular compartments. In this study, we determined the proteome-wide signatures of the RPD3/HDA1 class of histone deacetylases in Arabidopsis Relative quantification of the changes in the lysine acetylation levels was determined on a proteome-wide scale after treatment of Arabidopsis leaves with deacetylase inhibitors apicidin and trichostatin A...
October 23, 2017: Molecular Systems Biology
Jaydeep K Srimani, Shuqiang Huang, Allison J Lopatkin, Lingchong You
The postantibiotic effect (PAE) refers to the temporary suppression of bacterial growth following transient antibiotic treatment. This effect has been observed for decades for a wide variety of antibiotics and microbial species. However, despite empirical observations, a mechanistic understanding of this phenomenon is lacking. Using a combination of modeling and quantitative experiments, we show that the PAE can be explained by the temporal dynamics of drug detoxification in individual cells after an antibiotic is removed from the extracellular environment...
October 23, 2017: Molecular Systems Biology
Michael J Lawson, Daniel Camsund, Jimmy Larsson, Özden Baltekin, David Fange, Johan Elf
In this work, we present a proof-of-principle experiment that extends advanced live cell microscopy to the scale of pool-generated strain libraries. We achieve this by identifying the genotypes for individual cells in situ after a detailed characterization of the phenotype. The principle is demonstrated by single-molecule fluorescence time-lapse imaging of Escherichia coli strains harboring barcoded plasmids that express a sgRNA which suppresses different genes in the E. coli genome through dCas9 interference...
October 17, 2017: Molecular Systems Biology
Carmelo Ferrai, Elena Torlai Triglia, Jessica R Risner-Janiczek, Tiago Rito, Owen Jl Rackham, Inês de Santiago, Alexander Kukalev, Mario Nicodemi, Altuna Akalin, Meng Li, Mark A Ungless, Ana Pombo
Polycomb repression in mouse embryonic stem cells (ESCs) is tightly associated with promoter co-occupancy of RNA polymerase II (RNAPII) which is thought to prime genes for activation during early development. However, it is unknown whether RNAPII poising is a general feature of Polycomb repression, or is lost during differentiation. Here, we map the genome-wide occupancy of RNAPII and Polycomb from pluripotent ESCs to non-dividing functional dopaminergic neurons. We find that poised RNAPII complexes are ubiquitously present at Polycomb-repressed genes at all stages of neuronal differentiation...
October 16, 2017: Molecular Systems Biology
Bernhard Schmierer, Sandeep K Botla, Jilin Zhang, Mikko Turunen, Teemu Kivioja, Jussi Taipale
Loss-of-function screening by CRISPR/Cas9 gene knockout with pooled, lentiviral guide libraries is a widely applicable method for systematic identification of genes contributing to diverse cellular phenotypes. Here, Random Sequence Labels (RSLs) are incorporated into the guide library, which act as unique molecular identifiers (UMIs) to allow massively parallel lineage tracing and lineage dropout screening. RSLs greatly improve the reproducibility of results by increasing both the precision and the accuracy of screens...
October 9, 2017: Molecular Systems Biology
Míriam Tarrado-Castellarnau, Pedro de Atauri, Josep Tarragó-Celada, Jordi Perarnau, Mariia Yuneva, Timothy M Thomson, Marta Cascante
Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through metabolic and transcriptomic analyses, we show that the inhibition of CDK4/6 leads to a metabolic reprogramming associated with gene networks orchestrated by the MYC transcription factor. Upon inhibition of CDK4/6, an accumulation of MYC protein ensues which explains an increased glutamine metabolism, activation of the mTOR pathway and blunting of HIF-1α-mediated responses to hypoxia...
October 4, 2017: Molecular Systems Biology
Julio M Belmonte, Maria Leptin, François Nédélec
Morphogenesis in animal tissues is largely driven by actomyosin networks, through tensions generated by an active contractile process. Although the network components and their properties are known, and networks can be reconstituted in vitro, the requirements for contractility are still poorly understood. Here, we describe a theory that predicts whether an isotropic network will contract, expand, or conserve its dimensions. This analytical theory correctly predicts the behavior of simulated networks, consisting of filaments with varying combinations of connectors, and reveals conditions under which networks of rigid filaments are either contractile or expansile...
September 27, 2017: Molecular Systems Biology
Laurence D Hurst
No abstract text is available yet for this article.
September 26, 2017: Molecular Systems Biology
Philipp E Geyer, Lesca M Holdt, Daniel Teupser, Matthias Mann
Clinical analysis of blood is the most widespread diagnostic procedure in medicine, and blood biomarkers are used to categorize patients and to support treatment decisions. However, existing biomarkers are far from comprehensive and often lack specificity and new ones are being developed at a very slow rate. As described in this review, mass spectrometry (MS)-based proteomics has become a powerful technology in biological research and it is now poised to allow the characterization of the plasma proteome in great depth...
September 26, 2017: Molecular Systems Biology
Florian Uhlitz, Anja Sieber, Emanuel Wyler, Raphaela Fritsche-Guenther, Johannes Meisig, Markus Landthaler, Bertram Klinger, Nils Blüthgen
No abstract text is available yet for this article.
September 25, 2017: Molecular Systems Biology
Luke S Tain, Robert Sehlke, Chirag Jain, Manopriya Chokkalingam, Nagarjuna Nagaraj, Paul Essers, Mark Rassner, Sebastian Grönke, Jenny Froelich, Christoph Dieterich, Matthias Mann, Nazif Alic, Andreas Beyer, Linda Partridge
Lowered activity of the insulin/IGF signalling (IIS) network can ameliorate the effects of ageing in laboratory animals and, possibly, humans. Although transcriptome remodelling in long-lived IIS mutants has been extensively documented, the causal mechanisms contributing to extended lifespan, particularly in specific tissues, remain unclear. We have characterized the proteomes of four key insulin-sensitive tissues in a long-lived Drosophila IIS mutant and control, and detected 44% of the predicted proteome (6,085 proteins)...
September 15, 2017: Molecular Systems Biology
Georg Kustatscher, Piotr Grabowski, Juri Rappsilber
Genes are not randomly distributed in the genome. In humans, 10% of protein-coding genes are transcribed from bidirectional promoters and many more are organised in larger clusters. Intriguingly, neighbouring genes are frequently coexpressed but rarely functionally related. Here we show that coexpression of bidirectional gene pairs, and closeby genes in general, is buffered at the protein level. Taking into account the 3D architecture of the genome, we find that co-regulation of spatially close, functionally unrelated genes is pervasive at the transcriptome level, but does not extend to the proteome...
August 23, 2017: Molecular Systems Biology
Sunjae Lee, Cheng Zhang, Zhengtao Liu, Martina Klevstig, Bani Mukhopadhyay, Mattias Bergentall, Resat Cinar, Marcus Ståhlman, Natasha Sikanic, Joshua K Park, Sumit Deshmukh, Azadeh M Harzandi, Tim Kuijpers, Morten Grøtli, Simon J Elsässer, Brian D Piening, Michael Snyder, Ulf Smith, Jens Nielsen, Fredrik Bäckhed, George Kunos, Mathias Uhlen, Jan Boren, Adil Mardinoglu
We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co-expression networks (CNs) for 46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver-specific genes co-expressed with fatty acid synthase (FASN)...
August 21, 2017: Molecular Systems Biology
Benjamín J Sánchez, Cheng Zhang, Avlant Nilsson, Petri-Jaan Lahtvee, Eduard J Kerkhoven, Jens Nielsen
Genome-scale metabolic models (GEMs) are widely used to calculate metabolic phenotypes. They rely on defining a set of constraints, the most common of which is that the production of metabolites and/or growth are limited by the carbon source uptake rate. However, enzyme abundances and kinetics, which act as limitations on metabolic fluxes, are not taken into account. Here, we present GECKO, a method that enhances a GEM to account for enzymes as part of reactions, thereby ensuring that each metabolic flux does not exceed its maximum capacity, equal to the product of the enzyme's abundance and turnover number...
August 3, 2017: Molecular Systems Biology
Panagiotis L Kastritis, Francis J O'Reilly, Thomas Bock, Yuanyue Li, Matt Z Rogon, Katarzyna Buczak, Natalie Romanov, Matthew J Betts, Khanh Huy Bui, Wim J Hagen, Marco L Hennrich, Marie-Therese Mackmull, Juri Rappsilber, Robert B Russell, Peer Bork, Martin Beck, Anne-Claude Gavin
The arrangement of proteins into complexes is a key organizational principle for many cellular functions. Although the topology of many complexes has been systematically analyzed in isolation, their molecular sociology in situ remains elusive. Here, we show that crude cellular extracts of a eukaryotic thermophile, Chaetomium thermophilum, retain basic principles of cellular organization. Using a structural proteomics approach, we simultaneously characterized the abundance, interactions, and structure of a third of the C...
July 25, 2017: Molecular Systems Biology
Albi Celaj, Ulrich Schlecht, Justin D Smith, Weihong Xu, Sundari Suresh, Molly Miranda, Ana Maria Aparicio, Michael Proctor, Ronald W Davis, Frederick P Roth, Robert P St Onge
Many cellular functions are mediated by protein-protein interaction networks, which are environment dependent. However, systematic measurement of interactions in diverse environments is required to better understand the relative importance of different mechanisms underlying network dynamics. To investigate environment-dependent protein complex dynamics, we used a DNA-barcode-based multiplexed protein interaction assay in Saccharomyces cerevisiae to measure in vivo abundance of 1,379 binary protein complexes under 14 environments...
July 13, 2017: Molecular Systems Biology
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