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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
C Gustavo Pesce, Stefan Zdraljevic, William J Peria, Alan Bush, María Victoria Repetto, Daniel Rockwell, Richard C Yu, Alejandro Colman-Lerner, Roger Brent
Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 "variability genes". Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct "axes" of system behavior...
April 4, 2018: Molecular Systems Biology
Thomas Lemberger
No abstract text is available yet for this article.
April 3, 2018: Molecular Systems Biology
Galit Alter, Karen G Dowell, Eric P Brown, Todd J Suscovich, Anastassia Mikhailova, Alison E Mahan, Bruce D Walker, Falk Nimmerjahn, Chris Bailey-Kellogg, Margaret E Ackerman
Defining correlates of immunity by comprehensively interrogating the extensive biological diversity in naturally or experimentally protected subjects may provide insights critical for guiding the development of effective vaccines and antibody-based therapies. We report advances in a humoral immunoprofiling approach and its application to elucidate hallmarks of effective HIV-1 viral control. Systematic serological analysis for a cohort of HIV-infected subjects with varying viral control was conducted using both a high-resolution, high-throughput biophysical antibody profiling approach, providing unbiased dissection of the humoral response, along with functional antibody assays, characterizing antibody-directed effector functions such as complement fixation and phagocytosis that are central to protective immunity...
March 26, 2018: Molecular Systems Biology
Seth A Ament, Jocelynn R Pearl, Jeffrey P Cantle, Robert M Bragg, Peter J Skene, Sydney R Coffey, Dani E Bergey, Vanessa C Wheeler, Marcy E MacDonald, Nitin S Baliga, Jim Rosinski, Leroy E Hood, Jeffrey B Carroll, Nathan D Price
Transcriptional changes occur presymptomatically and throughout Huntington's disease (HD), motivating the study of transcriptional regulatory networks (TRNs) in HD We reconstructed a genome-scale model for the target genes of 718 transcription factors (TFs) in the mouse striatum by integrating a model of genomic binding sites with transcriptome profiling of striatal tissue from HD mouse models. We identified 48 differentially expressed TF-target gene modules associated with age- and CAG repeat length-dependent gene expression changes in Htt CAG knock-in mouse striatum and replicated many of these associations in independent transcriptomic and proteomic datasets...
March 26, 2018: Molecular Systems Biology
Marija Buljan, Peter Blattmann, Ruedi Aebersold, Michael Boutros
Cancer genome sequencing has shown that driver genes can often be distinguished not only by the elevated mutation frequency but also by specific nucleotide positions that accumulate changes at a high rate. However, properties associated with a residue's potential to drive tumorigenesis when mutated have not yet been systematically investigated. Here, using a novel methodological approach, we identify and characterize a compendium of 180 hotspot residues within 160 human proteins which occur with a significant frequency and are likely to have functionally relevant impact...
March 23, 2018: Molecular Systems Biology
Shiwei Zheng, Efthymia Papalexi, Andrew Butler, William Stephenson, Rahul Satija
Hematopoietic stem cells (HSCs) give rise to diverse cell types in the blood system, yet our molecular understanding of the early trajectories that generate this enormous diversity in humans remains incomplete. Here, we leverage Drop-seq, a massively parallel single-cell RNA sequencing (scRNA-seq) approach, to individually profile 20,000 progenitor cells from human cord blood, without prior enrichment or depletion for individual lineages based on surface markers. Our data reveal a transcriptional compendium of progenitor states in human cord blood, representing four committed lineages downstream from HSC, alongside the transcriptional dynamics underlying fate commitment...
March 15, 2018: Molecular Systems Biology
Antoine Vigouroux, Enno Oldewurtel, Lun Cui, David Bikard, Sven van Teeffelen
Over the past few years, tools that make use of the Cas9 nuclease have led to many breakthroughs, including in the control of gene expression. The catalytically dead variant of Cas9 known as dCas9 can be guided by small RNAs to block transcription of target genes, in a strategy also known as CRISPRi. Here, we reveal that the level of complementarity between the guide RNA and the target controls the rate at which RNA polymerase "kicks out" dCas9 from the target and completes transcription. We use this mechanism to precisely and robustly reduce gene expression by defined relative amounts...
March 8, 2018: Molecular Systems Biology
Alireza Azimi, Stefano Caramuta, Brinton Seashore-Ludlow, Johan Boström, Jonathan L Robinson, Fredrik Edfors, Rainer Tuominen, Kristel Kemper, Oscar Krijgsman, Daniel S Peeper, Jens Nielsen, Johan Hansson, Suzanne Egyhazi Brage, Mikael Altun, Mathias Uhlen, Gianluca Maddalo
Novel therapies are undergoing clinical trials, for example, the Hsp90 inhibitor, XL888, in combination with BRAF inhibitors for the treatment of therapy-resistant melanomas. Unfortunately, our data show that this combination elicits a heterogeneous response in a panel of melanoma cell lines including PDX-derived models. We sought to understand the mechanisms underlying the differential responses and suggest a patient stratification strategy. Thermal proteome profiling (TPP) identified the protein targets of XL888 in a pair of sensitive and unresponsive cell lines...
March 5, 2018: Molecular Systems Biology
Jérôme Salignon, Magali Richard, Etienne Fulcrand, Hélène Duplus-Bottin, Gaël Yvert
Living systems control cell growth dynamically by processing information from their environment. Although responses to a single environmental change have been intensively studied, little is known about how cells react to fluctuating conditions. Here, we address this question at the genomic scale by measuring the relative proliferation rate (fitness) of 3,568 yeast gene deletion mutants in out-of-equilibrium conditions: periodic oscillations between two environmental conditions. In periodic salt stress, fitness and its genetic variance largely depended on the oscillating period...
March 5, 2018: Molecular Systems Biology
Daniel D Seaton, Alexander Graf, Katja Baerenfaller, Mark Stitt, Andrew J Millar, Wilhelm Gruissem
Plants respond to seasonal cues such as the photoperiod, to adapt to current conditions and to prepare for environmental changes in the season to come. To assess photoperiodic responses at the protein level, we quantified the proteome of the model plant Arabidopsis thaliana by mass spectrometry across four photoperiods. This revealed coordinated changes of abundance in proteins of photosynthesis, primary and secondary metabolism, including pigment biosynthesis, consistent with higher metabolic activity in long photoperiods...
March 1, 2018: Molecular Systems Biology
Christoph Fritzsch, Stephan Baumgärtner, Monika Kuban, Daria Steinshorn, George Reid, Stefan Legewie
Cellular decision-making and environmental adaptation are dependent upon a heterogeneous response of gene expression to external cues. Heterogeneity arises in transcription from random switching between transcriptionally active and inactive states, resulting in bursts of RNA synthesis. Furthermore, the cellular state influences the competency of transcription, thereby globally affecting gene expression in a cell-specific manner. We determined how external stimuli interplay with cellular state to modulate the kinetics of bursting...
February 23, 2018: Molecular Systems Biology
H Tomas Rube, Chaitanya Rastogi, Judith F Kribelbauer, Harmen J Bussemaker
Transcription factors (TFs) interpret DNA sequence by probing the chemical and structural properties of the nucleotide polymer. DNA shape is thought to enable a parsimonious representation of dependencies between nucleotide positions. Here, we propose a unified mathematical representation of the DNA sequence dependence of shape and TF binding, respectively, which simplifies and enhances analysis of shape readout. First, we demonstrate that linear models based on mononucleotide features alone account for 60-70% of the variance in minor groove width, roll, helix twist, and propeller twist...
February 22, 2018: Molecular Systems Biology
Benedikt Rauscher, Florian Heigwer, Luisa Henkel, Thomas Hielscher, Oksana Voloshanenko, Michael Boutros
Cancer genomes often harbor hundreds of molecular aberrations. Such genetic variants can be drivers or passengers of tumorigenesis and create vulnerabilities for potential therapeutic exploitation. To identify genotype-dependent vulnerabilities, forward genetic screens in different genetic backgrounds have been conducted. We devised MINGLE, a computational framework to integrate CRISPR/Cas9 screens originating from different libraries building on approaches pioneered for genetic network discovery in model organisms...
February 21, 2018: Molecular Systems Biology
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