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Molecular Systems Biology

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
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
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
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
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
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
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
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
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
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
Malene L Urbanus, Andrew T Quaile, Peter J Stogios, Mariya Morar, Chitong Rao, Rosa Di Leo, Elena Evdokimova, Mandy Lam, Christina Oatway, Marianne E Cuff, Jerzy Osipiuk, Karolina Michalska, Boguslaw P Nocek, Mikko Taipale, Alexei Savchenko, Alexander W Ensminger
Pathogens deliver complex arsenals of translocated effector proteins to host cells during infection, but the extent to which these proteins are regulated once inside the eukaryotic cell remains poorly defined. Among all bacterial pathogens, Legionella pneumophila maintains the largest known set of translocated substrates, delivering over 300 proteins to the host cell via its Type IVB, Icm/Dot translocation system. Backed by a few notable examples of effector-effector regulation in L. pneumophila, we sought to define the extent of this phenomenon through a systematic analysis of effector-effector functional interaction...
December 16, 2016: Molecular Systems Biology
Jason Yao, Anna Pilko, Roy Wollman
The heterogeneity in mammalian cells signaling response is largely a result of pre-existing cell-to-cell variability. It is unknown whether cell-to-cell variability rises from biochemical stochastic fluctuations or distinct cellular states. Here, we utilize calcium response to adenosine trisphosphate as a model for investigating the structure of heterogeneity within a population of cells and analyze whether distinct cellular response states coexist. We use a functional definition of cellular state that is based on a mechanistic dynamical systems model of calcium signaling...
December 15, 2016: Molecular Systems Biology
Arne B Gjuvsland, Enikö Zörgö, Jeevan Ka Samy, Simon Stenberg, Ibrahim H Demirsoy, Francisco Roque, Ewa Maciaszczyk-Dziubinska, Magdalena Migocka, Elisa Alonso-Perez, Martin Zackrisson, Robert Wysocki, Markus J Tamás, Inge Jonassen, Stig W Omholt, Jonas Warringer
A major rationale for the advocacy of epigenetically mediated adaptive responses is that they facilitate faster adaptation to environmental challenges. This motivated us to develop a theoretical-experimental framework for disclosing the presence of such adaptation-speeding mechanisms in an experimental evolution setting circumventing the need for pursuing costly mutation-accumulation experiments. To this end, we exposed clonal populations of budding yeast to a whole range of stressors. By growth phenotyping, we found that almost complete adaptation to arsenic emerged after a few mitotic cell divisions without involving any phenotypic plasticity...
December 15, 2016: Molecular Systems Biology
M Jordan Rowley, Victor G Corces
No abstract text is available yet for this article.
December 9, 2016: Molecular Systems Biology
Lilija Brant, Theodore Georgomanolis, Milos Nikolic, Chris A Brackley, Petros Kolovos, Wilfred van Ijcken, Frank G Grosveld, Davide Marenduzzo, Argyris Papantonis
Mammalian interphase chromosomes fold into a multitude of loops to fit the confines of cell nuclei, and looping is tightly linked to regulated function. Chromosome conformation capture (3C) technology has significantly advanced our understanding of this structure-to-function relationship. However, all 3C-based methods rely on chemical cross-linking to stabilize spatial interactions. This step remains a "black box" as regards the biases it may introduce, and some discrepancies between microscopy and 3C studies have now been reported...
December 9, 2016: Molecular Systems Biology
Mei-Sheng Xiao, Bin Zhang, Yi-Sheng Li, Qingsong Gao, Wei Sun, Wei Chen
Alternative polyadenylation (APA), which is regulated by both cis-elements and trans-factors, plays an important role in post-transcriptional regulation of eukaryotic gene expression. However, comparing to the extensively studied transcription and alternative splicing, the extent of APA divergence during evolution and the relative cis- and trans-contribution remain largely unexplored. To directly address these questions for the first time in mammals, by using deep sequencing-based methods, we measured APA divergence between C57BL/6J and SPRET/EiJ mouse strains as well as allele-specific APA pattern in their F1 hybrids...
December 8, 2016: Molecular Systems Biology
David Ochoa, Mindaugas Jonikas, Robert T Lawrence, Bachir El Debs, Joel Selkrig, Athanasios Typas, Judit Villén, Silvia Dm Santos, Pedro Beltrao
The coordinated regulation of protein kinases is a rapid mechanism that integrates diverse cues and swiftly determines appropriate cellular responses. However, our understanding of cellular decision-making has been limited by the small number of simultaneously monitored phospho-regulatory events. Here, we have estimated changes in activity in 215 human kinases in 399 conditions derived from a large compilation of phosphopeptide quantifications. This atlas identifies commonly regulated kinases as those that are central in the signaling network and defines the logic relationships between kinase pairs...
December 1, 2016: Molecular Systems Biology
Sören Müller, Siyuan John Liu, Elizabeth Di Lullo, Martina Malatesta, Alex A Pollen, Tomasz J Nowakowski, Gary Kohanbash, Manish Aghi, Arnold R Kriegstein, Daniel A Lim, Aaron Diaz
Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) receptors are frequently amplified and/or possess gain-of-function mutations in GBM However, clinical trials of tyrosine-kinase inhibitors have shown disappointing efficacy, in part due to intra-tumor heterogeneity. To assess the effect of clonal heterogeneity on gene expression, we derived an approach to map single-cell expression profiles to sequentially acquired mutations identified from exome sequencing...
November 25, 2016: Molecular Systems Biology
Dalila Bensaddek, Angus I Lamond
No abstract text is available yet for this article.
November 10, 2016: Molecular Systems Biology
Omer Karin, Avital Swisa, Benjamin Glaser, Yuval Dor, Uri Alon
Biological systems can maintain constant steady-state output despite variation in biochemical parameters, a property known as exact adaptation. Exact adaptation is achieved using integral feedback, an engineering strategy that ensures that the output of a system robustly tracks its desired value. However, it is unclear how physiological circuits also keep their output dynamics precise-including the amplitude and response time to a changing input. Such robustness is crucial for endocrine and neuronal homeostatic circuits because they need to provide a precise dynamic response in the face of wide variation in the physiological parameters of their target tissues; how such circuits compensate their dynamics for unavoidable natural fluctuations in parameters is unknown...
November 8, 2016: Molecular Systems Biology
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