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Molecular Systems Biology

Héloïse Muller, Vittore F Scolari, Nicolas Agier, Aurèle Piazza, Agnès Thierry, Guillaume Mercy, Stéphane Descorps-Declere, Luciana Lazar-Stefanita, Olivier Espeli, Bertrand Llorente, Gilles Fischer, Julien Mozziconacci, Romain Koszul
In chromosome conformation capture experiments (Hi-C), the accuracy with which contacts are detected varies due to the uneven distribution of restriction sites along genomes. In addition, repeated sequences or homologous regions remain indistinguishable because of the ambiguities they introduce during the alignment of the sequencing reads. We addressed both limitations by designing and engineering 144 kb of a yeast chromosome with regularly spaced restriction sites (Syn-HiC design). In the Syn-HiC region, Hi-C signal-to-noise ratio is enhanced and can be used to measure the shape of an unbiased distribution of contact frequencies, allowing to propose a robust definition of a Hi-C experiment resolution...
July 16, 2018: Molecular Systems Biology
Philipp Trepte, Sabrina Kruse, Simona Kostova, Sheila Hoffmann, Alexander Buntru, Anne Tempelmeier, Christopher Secker, Lisa Diez, Aline Schulz, Konrad Klockmeier, Martina Zenkner, Sabrina Golusik, Kirstin Rau, Sigrid Schnoegl, Craig C Garner, Erich E Wanker
Information on protein-protein interactions (PPIs) is of critical importance for studying complex biological systems and developing therapeutic strategies. Here, we present a double-readout bioluminescence-based two-hybrid technology, termed LuTHy, which provides two quantitative scores in one experimental procedure when testing binary interactions. PPIs are first monitored in cells by quantification of bioluminescence resonance energy transfer (BRET) and, following cell lysis, are again quantitatively assessed by luminescence-based co-precipitation (LuC)...
July 11, 2018: Molecular Systems Biology
André Mateus, Jacob Bobonis, Nils Kurzawa, Frank Stein, Dominic Helm, Johannes Hevler, Athanasios Typas, Mikhail M Savitski
Increasing antibiotic resistance urges for new technologies for studying microbes and antimicrobial mechanism of action. We adapted thermal proteome profiling (TPP) to probe the thermostability of Escherichia coli proteins in vivo E. coli had a more thermostable proteome than human cells, with protein thermostability depending on subcellular location-forming a high-to-low gradient from the cell surface to the cytoplasm. While subunits of protein complexes residing in one compartment melted similarly, protein complexes spanning compartments often had their subunits melting in a location-wise manner...
July 6, 2018: Molecular Systems Biology
Luca Parca, Martin Beck, Peer Bork, Alessandro Ori
Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested...
July 2, 2018: Molecular Systems Biology
Rik Gh Lindeboom, Lisa van Voorthuijsen, Koen C Oost, Maria J Rodríguez-Colman, Maria V Luna-Velez, Cristina Furlan, Floriane Baraille, Pascal Wtc Jansen, Agnès Ribeiro, Boudewijn Mt Burgering, Hugo J Snippert, Michiel Vermeulen
Intestinal organoids accurately recapitulate epithelial homeostasis in vivo , thereby representing a powerful in vitro system to investigate lineage specification and cellular differentiation. Here, we applied a multi-omics framework on stem cell-enriched and stem cell-depleted mouse intestinal organoids to obtain a holistic view of the molecular mechanisms that drive differential gene expression during adult intestinal stem cell differentiation. Our data revealed a global rewiring of the transcriptome and proteome between intestinal stem cells and enterocytes, with the majority of dynamic protein expression being transcription-driven...
June 26, 2018: Molecular Systems Biology
Manuel Campos, Sander K Govers, Irnov Irnov, Genevieve S Dobihal, François Cornet, Christine Jacobs-Wagner
Cell size, cell growth, and cell cycle events are necessarily intertwined to achieve robust bacterial replication. Yet, a comprehensive and integrated view of these fundamental processes is lacking. Here, we describe an image-based quantitative screen of the single-gene knockout collection of Escherichia coli and identify many new genes involved in cell morphogenesis, population growth, nucleoid (bulk chromosome) dynamics, and cell division. Functional analyses, together with high-dimensional classification, unveil new associations of morphological and cell cycle phenotypes with specific functions and pathways...
June 25, 2018: Molecular Systems Biology
Clare Abreu, Anthony Ortiz Lopez, Jeff Gore
No abstract text is available yet for this article.
June 21, 2018: Molecular Systems Biology
Ophelia S Venturelli, Alex C Carr, Garth Fisher, Ryan H Hsu, Rebecca Lau, Benjamin P Bowen, Susan Hromada, Trent Northen, Adam P Arkin
The ecological forces that govern the assembly and stability of the human gut microbiota remain unresolved. We developed a generalizable model-guided framework to predict higher-dimensional consortia from time-resolved measurements of lower-order assemblages. This method was employed to decipher microbial interactions in a diverse human gut microbiome synthetic community. We show that pairwise interactions are major drivers of multi-species community dynamics, as opposed to higher-order interactions. The inferred ecological network exhibits a high proportion of negative and frequent positive interactions...
June 21, 2018: Molecular Systems Biology
Ricard Argelaguet, Britta Velten, Damien Arnol, Sascha Dietrich, Thorsten Zenz, John C Marioni, Florian Buettner, Wolfgang Huber, Oliver Stegle
Multi-omics studies promise the improved characterization of biological processes across molecular layers. However, methods for the unsupervised integration of the resulting heterogeneous data sets are lacking. We present Multi-Omics Factor Analysis (MOFA), a computational method for discovering the principal sources of variation in multi-omics data sets. MOFA infers a set of (hidden) factors that capture biological and technical sources of variability. It disentangles axes of heterogeneity that are shared across multiple modalities and those specific to individual data modalities...
June 20, 2018: Molecular Systems Biology
Alexis Courbet, Patrick Amar, François Fages, Eric Renard, Franck Molina
No abstract text is available yet for this article.
June 1, 2018: Molecular Systems Biology
Alvaro Rada-Iglesias, Frank G Grosveld, Argyris Papantonis
The last decade has radically renewed our understanding of higher order chromatin folding in the eukaryotic nucleus. As a result, most current models are in support of a mostly hierarchical and relatively stable folding of chromosomes dividing chromosomal territories into A- (active) and B- (inactive) compartments, which are then further partitioned into topologically associating domains (TADs), each of which is made up from multiple loops stabilized mainly by the CTCF and cohesin chromatin-binding complexes...
June 1, 2018: Molecular Systems Biology
J Javier Díaz-Mejía, Albi Celaj, Joseph C Mellor, Atina Coté, Attila Balint, Brandon Ho, Pritpal Bansal, Fatemeh Shaeri, Marinella Gebbia, Jochen Weile, Marta Verby, Anna Karkhanina, YiFan Zhang, Cassandra Wong, Justin Rich, D'Arcy Prendergast, Gaurav Gupta, Sedide Öztürk, Daniel Durocher, Grant W Brown, Frederick P Roth
Condition-dependent genetic interactions can reveal functional relationships between genes that are not evident under standard culture conditions. State-of-the-art yeast genetic interaction mapping, which relies on robotic manipulation of arrays of double-mutant strains, does not scale readily to multi-condition studies. Here, we describe barcode fusion genetics to map genetic interactions (BFG-GI), by which double-mutant strains generated via en masse "party" mating can also be monitored en masse for growth to detect genetic interactions...
May 28, 2018: Molecular Systems Biology
Muhammad Ali, Ylva Ivarsson
No abstract text is available yet for this article.
May 22, 2018: Molecular Systems Biology
Steven Timmermans, Claude Libert
No abstract text is available yet for this article.
May 17, 2018: Molecular Systems Biology
Rose B Joachim, Gabriel M Altschuler, John N Hutchinson, Hector R Wong, Winston A Hide, Lester Kobzik
Attempts to develop drugs that address sepsis based on leads developed in animal models have failed. We sought to identify leads based on human data by exploiting a natural experiment: the relative resistance of children to mortality from severe infections and sepsis. Using public datasets, we identified key differences in pathway activity (Pathprint) in blood transcriptome profiles of septic adults and children. To find drugs that could promote beneficial (child) pathways or inhibit harmful (adult) ones, we built an in silico pathway drug network (PDN) using expression correlation between drug, disease, and pathway gene signatures across 58,475 microarrays...
May 17, 2018: Molecular Systems Biology
Charles Nj Ravarani, Tamara Y Erkina, Greet De Baets, Daniel C Dudman, Alexandre M Erkine, M Madan Babu
Over 40% of proteins in any eukaryotic genome encode intrinsically disordered regions (IDRs) that do not adopt defined tertiary structures. Certain IDRs perform critical functions, but discovering them is non-trivial as the biological context determines their function. We present IDR-Screen, a framework to discover functional IDRs in a high-throughput manner by simultaneously assaying large numbers of DNA sequences that code for short disordered sequences. Functionality-conferring patterns in their protein sequence are inferred through statistical learning...
May 14, 2018: Molecular Systems Biology
Kyle M Kovary, Brooks Taylor, Michael L Zhao, Mary N Teruel
Due to noise in the synthesis and degradation of proteins, the concentrations of individual vertebrate signaling proteins were estimated to vary with a coefficient of variation (CV) of approximately 25% between cells. Such high variation is beneficial for population-level regulation of cell functions but abolishes accurate single-cell signal transmission. Here, we measure cell-to-cell variability of relative protein abundance using quantitative proteomics of individual Xenopus laevis eggs and cultured human cells and show that variation is typically much lower, in the range of 5-15%, compatible with accurate single-cell transmission...
May 14, 2018: Molecular Systems Biology
Alexis Courbet, Patrick Amar, François Fages, Eric Renard, Franck Molina
Biological systems have evolved efficient sensing and decision-making mechanisms to maximize fitness in changing molecular environments. Synthetic biologists have exploited these capabilities to engineer control on information and energy processing in living cells. While engineered organisms pose important technological and ethical challenges, de novo assembly of non-living biomolecular devices could offer promising avenues toward various real-world applications. However, assembling biochemical parts into functional information processing systems has remained challenging due to extensive multidimensional parameter spaces that must be sampled comprehensively in order to identify robust, specification compliant molecular implementations...
April 26, 2018: Molecular Systems Biology
Delphine Aymoz, Carme Solé, Jean-Jerrold Pierre, Marta Schmitt, Eulàlia de Nadal, Francesc Posas, Serge Pelet
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...
April 25, 2018: Molecular Systems Biology
Jonathan A Griffiths, Antonio Scialdone, John C Marioni
High-throughput -omics techniques have revolutionised biology, allowing for thorough and unbiased characterisation of the molecular states of biological systems. However, cellular decision-making is inherently a unicellular process to which "bulk" -omics techniques are poorly suited, as they capture ensemble averages of cell states. Recently developed single-cell methods bridge this gap, allowing high-throughput molecular surveys of individual cells. In this review, we cover core concepts of analysis of single-cell gene expression data and highlight areas of developmental biology where single-cell techniques have made important contributions...
April 16, 2018: Molecular Systems Biology
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