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Molecular Systems Biology

Karin Mitosch, Georg Rieckh, Tobias Bollenbach
Sudden stress often triggers diverse, temporally structured gene expression responses in microbes, but it is largely unknown how variable in time such responses are and if genes respond in the same temporal order in every single cell. Here, we quantified timing variability of individual promoters responding to sublethal antibiotic stress using fluorescent reporters, microfluidics, and time-lapse microscopy. We identified lower and upper bounds that put definite constraints on timing variability, which varies strongly among promoters and conditions...
February 14, 2019: Molecular Systems Biology
Sandra Cortijo, Zeynep Aydin, Sebastian Ahnert, James Cw Locke
A fundamental question in biology is how gene expression is regulated to give rise to a phenotype. However, transcriptional variability is rarely considered although it could influence the relationship between genotype and phenotype. It is known in unicellular organisms that gene expression is often noisy rather than uniform, and this has been proposed to be beneficial when environmental conditions are unpredictable. However, little is known about inter-individual transcriptional variability in multicellular organisms...
January 24, 2019: Molecular Systems Biology
Moritz Heusel, Isabell Bludau, George Rosenberger, Robin Hafen, Max Frank, Amir Banaei-Esfahani, Audrey van Drogen, Ben C Collins, Matthias Gstaiger, Ruedi Aebersold
Proteins are major effectors and regulators of biological processes that can elicit multiple functions depending on their interaction with other proteins. The organization of proteins into macromolecular complexes and their quantitative distribution across these complexes is, therefore, of great biological and clinical significance. In this paper, we describe an integrated experimental and computational technique to quantify hundreds of protein complexes in a single operation. The method consists of size exclusion chromatography (SEC) to fractionate native protein complexes, SWATH/DIA mass spectrometry to precisely quantify the proteins in each SEC fraction, and the computational framework CCprofiler to detect and quantify protein complexes by error-controlled, complex-centric analysis using prior information from generic protein interaction maps...
January 14, 2019: Molecular Systems Biology
Greg Slodkowicz, M Madan Babu
No abstract text is available yet for this article.
December 20, 2018: Molecular Systems Biology
Evan A Boyle, Jonathan K Pritchard, William J Greenleaf
Powerful new technologies for perturbing genetic elements have recently expanded the study of genetic interactions in model systems ranging from yeast to human cell lines. However, technical artifacts can confound signal across genetic screens and limit the immense potential of parallel screening approaches. To address this problem, we devised a novel PCA-based method for correcting genome-wide screening data, bolstering the sensitivity and specificity of detection for genetic interactions. Applying this strategy to a set of 436 whole genome CRISPR screens, we report more than 1...
December 20, 2018: Molecular Systems Biology
Omar Wagih, Marco Galardini, Bede P Busby, Danish Memon, Athanasios Typas, Pedro Beltrao
The effect of single nucleotide variants (SNVs) in coding and noncoding regions is of great interest in genetics. Although many computational methods aim to elucidate the effects of SNVs on cellular mechanisms, it is not straightforward to comprehensively cover different molecular effects. To address this, we compiled and benchmarked sequence and structure-based variant effect predictors and we computed the impact of nearly all possible amino acid and nucleotide variants in the reference genomes of Homo sapiens , Saccharomyces cerevisiae and Escherichia coli Studied mechanisms include protein stability, interaction interfaces, post-translational modifications and transcription factor binding sites...
December 20, 2018: Molecular Systems Biology
Thomas Lemberger
No abstract text is available yet for this article.
December 17, 2018: Molecular Systems Biology
Felix Moser, Amin Espah Borujeni, Amar N Ghodasara, Ewen Cameron, Yongjin Park, Christopher A Voigt
Controlling gene expression during a bioprocess enables real-time metabolic control, coordinated cellular responses, and staging order-of-operations. Achieving this with small molecule inducers is impractical at scale and dynamic circuits are difficult to design. Here, we show that the same set of sensors can be integrated by different combinatorial logic circuits to vary when genes are turned on and off during growth. Three Escherichia coli sensors that respond to the consumption of feedstock (glucose), dissolved oxygen, and by-product accumulation (acetate) are constructed and optimized...
November 27, 2018: Molecular Systems Biology
Marcelo C Bassalo, Andrew D Garst, Alaksh Choudhury, William C Grau, Eun J Oh, Eileen Spindler, Tanya Lipscomb, Ryan T Gill
Our limited ability to predict genotype-phenotype relationships has called for strategies that allow testing of thousands of hypotheses in parallel. Deep scanning mutagenesis has been successfully implemented to map genotype-phenotype relationships at a single-protein scale, allowing scientists to elucidate properties that are difficult to predict. However, most phenotypes are dictated by several proteins that are interconnected through complex and robust regulatory and metabolic networks. These sophisticated networks hinder our understanding of the phenotype of interest and limit our capabilities to rewire cellular functions...
November 26, 2018: Molecular Systems Biology
Weiming Yang, Minghui Ao, Yingwei Hu, Qing Kay Li, Hui Zhang
Protein glycosylation is one of the most abundant post-translational modifications. However, detailed analysis of O-linked glycosylation, a major type of protein glycosylation, has been severely impeded by the scarcity of suitable methodologies. Here, a chemoenzymatic method is introduced for the site-specific extraction of O-linked glycopeptides (EXoO), which enabled the mapping of over 3,000 O-linked glycosylation sites and definition of their glycans on over 1,000 proteins in human kidney tissues, T cells, and serum...
November 20, 2018: Molecular Systems Biology
Roxanne E Debaugny, Aurore Sanchez, Jérôme Rech, Delphine Labourdette, Jérôme Dorignac, Frédéric Geniet, John Palmeri, Andrea Parmeggiani, François Boudsocq, Véronique Anton Leberre, Jean-Charles Walter, Jean-Yves Bouet
Chromosome and plasmid segregation in bacteria are mostly driven by ParAB S systems. These DNA partitioning machineries rely on large nucleoprotein complexes assembled on centromere sites ( parS ). However, the mechanism of how a few parS -bound ParB proteins nucleate the formation of highly concentrated ParB clusters remains unclear despite several proposed physico-mathematical models. We discriminated between these different models by varying some key parameters in vivo using the F plasmid partition system...
November 16, 2018: Molecular Systems Biology
Karthik Sekar, Roberto Rusconi, John T Sauls, Tobias Fuhrer, Elad Noor, Jen Nguyen, Vicente I Fernandez, Marieke F Buffing, Michael Berney, Suckjoon Jun, Roman Stocker, Uwe Sauer
In natural environments, microbes are typically non-dividing and gauge when nutrients permit division. Current models are phenomenological and specific to nutrient-rich, exponentially growing cells, thus cannot predict the first division under limiting nutrient availability. To assess this regime, we supplied starving Escherichia coli with glucose pulses at increasing frequencies. Real-time metabolomics and microfluidic single-cell microscopy revealed unexpected, rapid protein, and nucleic acid synthesis already from minuscule glucose pulses in non-dividing cells...
November 5, 2018: Molecular Systems Biology
Chee Sheng Ng, Ameya Sinha, Yaw Aniweh, Qianhui Nah, Indrakanti Ramesh Babu, Chen Gu, Yok Hian Chionh, Peter C Dedon, Peter R Preiser
Among components of the translational machinery, ribonucleoside modifications on tRNAs are emerging as critical regulators of cell physiology and stress response. Here, we demonstrate highly coordinated behavior of the repertoire of tRNA modifications of Plasmodium falciparum throughout the intra-erythrocytic developmental cycle (IDC). We observed both a synchronized increase in 22 of 28 modifications from ring to trophozoite stage, consistent with tRNA maturation during translational up-regulation, and asynchronous changes in six modifications...
October 4, 2018: Molecular Systems Biology
Koji L Ode, Hiroki R Ueda
No abstract text is available yet for this article.
September 24, 2018: Molecular Systems Biology
Yolanda Schaerli, Alba Jiménez, José M Duarte, Ljiljana Mihajlovic, Julien Renggli, Mark Isalan, James Sharpe, Andreas Wagner
Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in Escherichia coli that produce a gene expression stripe-a pivotal pattern in embryonic development...
September 10, 2018: Molecular Systems Biology
Lucia Durrieu, Daniel Kirrmaier, Tatjana Schneidt, Ilia Kats, Sarada Raghavan, Lars Hufnagel, Timothy E Saunders, Michael Knop
Embryogenesis relies on instructions provided by spatially organized signaling molecules known as morphogens. Understanding the principles behind morphogen distribution and how cells interpret locally this information remains a major challenge in developmental biology. Here, we introduce morphogen-age measurements as a novel approach to test models of morphogen gradient formation. Using a tandem fluorescent timer as a protein age sensor, we find a gradient of increasing age of Bicoid along the anterior-posterior axis in the early Drosophila embryo...
September 4, 2018: Molecular Systems Biology
Samuel C Wolff, Katarzyna M Kedziora, Raluca Dumitru, Cierra D Dungee, Tarek M Zikry, Adriana S Beltran, Rachel A Haggerty, JrGang Cheng, Margaret A Redick, Jeremy E Purvis
It is well known that clonal cells can make different fate decisions, but it is unclear whether these decisions are determined during, or before, a cell's own lifetime. Here, we engineered an endogenous fluorescent reporter for the pluripotency factor OCT4 to study the timing of differentiation decisions in human embryonic stem cells. By tracking single-cell OCT4 levels over multiple cell cycle generations, we found that the decision to differentiate is largely determined before the differentiation stimulus is presented and can be predicted by a cell's preexisting OCT4 signaling patterns...
September 3, 2018: Molecular Systems Biology
Emanuel Rognoni, Angela Oliveira Pisco, Toru Hiratsuka, Kalle H Sipilä, Julio M Belmonte, Seyedeh Atefeh Mobasseri, Christina Philippeos, Rui Dilão, Fiona M Watt
Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here, we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual-tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing...
August 29, 2018: Molecular Systems Biology
Andrzej J Rzepiela, Souvik Ghosh, Jeremie Breda, Arnau Vina-Vilaseca, Afzal P Syed, Andreas J Gruber, Katja Eschbach, Christian Beisel, Erik van Nimwegen, Mihaela Zavolan
miRNAs are small RNAs that regulate gene expression post-transcriptionally. By repressing the translation and promoting the degradation of target mRNAs, miRNAs may reduce the cell-to-cell variability in protein expression, induce correlations between target expression levels, and provide a layer through which targets can influence each other's expression as "competing RNAs" (ceRNAs). However, experimental evidence for these behaviors is limited. Combining mathematical modeling with RNA sequencing of individual human embryonic kidney cells in which the expression of two distinct miRNAs was induced over a wide range, we have inferred parameters describing the response of hundreds of miRNA targets to miRNA induction...
August 27, 2018: Molecular Systems Biology
Daniela Michlmayr, Theodore R Pak, Adeeb H Rahman, El-Ad David Amir, Eun-Young Kim, Seunghee Kim-Schulze, Maria Suprun, Michael G Stewart, Guajira P Thomas, Angel Balmaseda, Li Wang, Jun Zhu, Mayte Suaréz-Fariñas, Steven M Wolinsky, Andrew Kasarskis, Eva Harris
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in "intermediate" CD14++ CD16+ monocytes and an activated subpopulation of CD14+ monocytes...
August 27, 2018: Molecular Systems Biology
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