Using cellular fitness to map the structure and function of a major facilitator superfamily effluxer
The major facilitator superfamily (MFS) effluxers are prominent mediators of antimicrobial resistance. The biochemical characterization of MFS proteins is hindered by their complex membrane environment that makes in vitro biochemical analysis challenging. Since the physicochemical properties of proteins drive the fitness of an organism, we posed the question of whether we could reverse that relationship and derive meaningful biochemical parameters for a single protein simply from fitness changes it confers under varying strengths of selection. Here, we present a physiological model that uses cellular fitness as a prox...
Source: Molecular Systems Biology - December 22, 2017 Category: Molecular Biology Authors: Perez, A. M., Gomez, M. M., Kalvapalle, P., O'Brien-Gilbert, E., Bennett, M. R., Shamoo, Y. Tags: Microbiology, Virology & Host Pathogen Interaction, Pharmacology & Drug Discovery, Quantitative Biology & Dynamical Systems Articles Source Type: research
A framework for exhaustively mapping functional missense variants
Although we now routinely sequence human genomes, we can confidently identify only a fraction of the sequence variants that have a functional impact. Here, we developed a deep mutational scanning framework that produces exhaustive maps for human missense variants by combining random codon mutagenesis and multiplexed functional variation assays with computational imputation and refinement. We applied this framework to four proteins corresponding to six human genes: UBE2I (encoding SUMO E2 conjugase), SUMO1 (small ubiquitin-like modifier), TPK1 (thiamin pyrophosphokinase), and CALM1/2/3 (three genes encoding the protein calm...
Source: Molecular Systems Biology - December 21, 2017 Category: Molecular Biology Authors: Weile, J., Sun, S., Cote, A. G., Knapp, J., Verby, M., Mellor, J. C., Wu, Y., Pons, C., Wong, C., van Lieshout, N., Yang, F., Tasan, M., Tan, G., Yang, S., Fowler, D. M., Nussbaum, R., Bloom, J. D., Vidal, M., Hill, D. E., Aloy, P., Roth, F. P. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Methods & Resources Source Type: research
Methods to drive systems biology forward
The development of new methodologies has driven the expansion of systems biology over the past decades. Technological breakthroughs in sequencing, in quantitative proteomics, in single-cell measurements, to name only a few, have each opened up whole new fields of research. To highlight the importance of new experimental and computational methodologies in enabling novel biological discoveries, we are pleased to announce the introduction of a new Methods section in Molecular Systems Biology (http://msb.embopress.org/authorguide#methodsguide). (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 21, 2017 Category: Molecular Biology Authors: Polychronidou, M., Lemberger, T. Tags: Methods & Resources Editorial Source Type: research
From network to phenotype: the dynamic wiring of an Arabidopsis transcriptional network induced by osmotic stress
This study resulted in the identification of a core network, composed of ERF6, ERF8, ERF9, ERF59, and ERF98, which is responsible for most transcriptional connections. The analyses highlight the biological function of this core network in environmental adaptation and its redundancy. Finally, a phenotypic analysis of loss-of-function and gain-of-function lines of the transcription factors established multiple connections between the stress-responsive network and leaf growth. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 21, 2017 Category: Molecular Biology Authors: Van den Broeck, L., Dubois, M., Vermeersch, M., Storme, V., Matsui, M., Inze, D. Tags: Genome-Scale & Integrative Biology, Plant Biology, Transcription Articles Source Type: research
Toward an understanding of the protein interaction network of the human liver
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 18, 2017 Category: Molecular Biology Authors: Wang, J., Huo, K., Ma, L., Tang, L., Li, D., Huang, X., Yuan, Y., Li, C., Wang, W., Guan, W., Chen, H., Jin, C., Wei, J., Zhang, W., Yang, Y., Liu, Q., Zhou, Y., Zhang, C., Wu, Z., Xu, W., Zhang, Y., Liu, T., Yu, D., Zhang, Y., Chen, L., Zhu, D., Zhong, X Tags: Corrigendum Source Type: research
Landscape of nuclear transport receptor cargo specificity
Nuclear transport receptors (NTRs) recognize localization signals of cargos to facilitate their passage across the central channel of nuclear pore complexes (NPCs). About 30 different NTRs constitute different transport pathways in humans and bind to a multitude of different cargos. The exact cargo spectrum of the majority of NTRs, their specificity and even the extent to which active nucleocytoplasmic transport contributes to protein localization remains understudied because of the transient nature of these interactions and the wide dynamic range of cargo concentrations. To systematically map cargo–NTR relationships...
Source: Molecular Systems Biology - December 18, 2017 Category: Molecular Biology Authors: Mackmull, M.-T., Klaus, B., Heinze, I., Chokkalingam, M., Beyer, A., Russell, R. B., Ori, A., Beck, M. Tags: Genome-Scale & Integrative Biology, Network Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Natural language processing: put your model where your mouth is
Molecular mechanisms are often described using "word models"—phrases intended to capture the interactions in a biological process. In their recent work, Sorger and colleagues (Gyori et al, 2017) provide a framework for converting word models into computational structures that can be simulated and compared to experimental data. By codifying word-based descriptions of molecular phenomena, scientific communities can better evaluate, compare, and share mechanistic insights. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - December 18, 2017 Category: Molecular Biology Authors: Haggerty, R. A., Purvis, J. E. Tags: Computational Biology, Methods & Resources, Signal Transduction News [amp ] Views Source Type: research
Subspecies in the global human gut microbiome
We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72% of the total assigned microbial abundance, single-nucleotide variation clearly indicates the existence of sub-populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identi...
Source: Molecular Systems Biology - December 14, 2017 Category: Molecular Biology Authors: Costea, P. I., Coelho, L. P., Sunagawa, S., Munch, R., Huerta-Cepas, J., Forslund, K., Hildebrand, F., Kushugulova, A., Zeller, G., Bork, P. Tags: Genome-Scale & Integrative Biology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
The landscape of human mutually exclusive splicing
Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than f...
Source: Molecular Systems Biology - December 14, 2017 Category: Molecular Biology Authors: Hatje, K., Rahman, R.-U., Vidal, R. O., Simm, D., Hammesfahr, B., Bansal, V., Rajput, A., Mickael, M. E., Sun, T., Bonn, S., Kollmar, M. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Transcription Articles Source Type: research
An integrated computational and experimental study uncovers FUT9 as a metabolic driver of colorectal cancer
Metabolic alterations play an important role in cancer and yet, few metabolic cancer driver genes are known. Here we perform a combined genomic and metabolic modeling analysis searching for metabolic drivers of colorectal cancer. Our analysis predicts FUT9, which catalyzes the biosynthesis of Ley glycolipids, as a driver of advanced-stage colon cancer. Experimental testing reveals FUT9's complex dual role; while its knockdown enhances proliferation and migration in monolayers, it suppresses colon cancer cells expansion in tumorspheres and inhibits tumor development in a mouse xenograft models. These results suggest that FU...
Source: Molecular Systems Biology - December 1, 2017 Category: Molecular Biology Authors: Auslander, N., Cunningham, C. E., Toosi, B. M., McEwen, E. J., Yizhak, K., Vizeacoumar, F. S., Parameswaran, S., Gonen, N., Freywald, T., Bhanumathy, K. K., Freywald, A., Vizeacoumar, F. J., Ruppin, E. Tags: Cancer, Genome-Scale & Integrative Biology, Metabolism Articles Source Type: research
Screening drug effects in patient-derived cancer cells links organoid responses to genome alterations
Cancer drug screening in patient-derived cells holds great promise for personalized oncology and drug discovery but lacks standardization. Whether cells are cultured as conventional monolayer or advanced, matrix-dependent organoid cultures influences drug effects and thereby drug selection and clinical success. To precisely compare drug profiles in differently cultured primary cells, we developed DeathPro, an automated microscopy-based assay to resolve drug-induced cell death and proliferation inhibition. Using DeathPro, we screened cells from ovarian cancer patients in monolayer or organoid culture with clinically relevan...
Source: Molecular Systems Biology - November 27, 2017 Category: Molecular Biology Authors: Jabs, J., Zickgraf, F. M., Park, J., Wagner, S., Jiang, X., Jechow, K., Kleinheinz, K., Toprak, U. H., Schneider, M. A., Meister, M., Spaich, S., Sütterlin, M., Schlesner, M., Trumpp, A., Sprick, M., Eils, R., Conrad, C. Tags: Cancer, Methods & Resources, Pharmacology & Drug Discovery Articles Source Type: research
From word models to executable models of signaling networks using automated assembly
We present an approach to building computational models directly from natural language using automated assembly. Molecular mechanisms described in simple English are read by natural language processing algorithms, converted into an intermediate representation, and assembled into executable or network models. We have implemented this approach in the Integrated Network and Dynamical Reasoning Assembler (INDRA), which draws on existing natural language processing systems as well as pathway information in Pathway Commons and other online resources. We demonstrate the use of INDRA and natural language to model three biological ...
Source: Molecular Systems Biology - November 24, 2017 Category: Molecular Biology Authors: Gyori, B. M., Bachman, J. A., Subramanian, K., Muhlich, J. L., Galescu, L., Sorger, P. K. Tags: Computational Biology, Methods & Resources, Signal Transduction Articles Source Type: research
Genetic circuit characterization and debugging using RNA-seq
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. Transcription profiles are obtained for all eight combinations of inputs, from which biophysica...
Source: Molecular Systems Biology - November 9, 2017 Category: Molecular Biology Authors: Gorochowski, T. E., Espah Borujeni, A., Park, Y., Nielsen, A. A., Zhang, J., Der, B. S., Gordon, D. B., Voigt, C. A. Tags: Genome-Scale & Integrative Biology, Synthetic Biology & Biotechnology Articles Source Type: research
Temporal fluxomics reveals oscillations in TCA cycle flux throughout the mammalian cell cycle
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. We find that TCA cycle fluxes are rewired as cells progress through the cell cycle with complementary oscillat...
Source: Molecular Systems Biology - November 6, 2017 Category: Molecular Biology Authors: Ahn, E., Kumar, P., Mukha, D., Tzur, A., Shlomi, T. Tags: Cell Cycle, Genome-Scale & Integrative Biology, Metabolism Articles Source Type: research
Pharmacoproteomic characterisation of human colon and rectal cancer
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. Modelling the responses of 52 CRC cell lines to 577 drugs as a function of proteome profiles enabled predictin...
Source: Molecular Systems Biology - November 3, 2017 Category: Molecular Biology Authors: Frejno, M., Zenezini Chiozzi, R., Wilhelm, M., Koch, H., Zheng, R., Klaeger, S., Ruprecht, B., Meng, C., Kramer, K., Jarzab, A., Heinzlmeir, S., Johnstone, E., Domingo, E., Kerr, D., Jesinghaus, M., Slotta-Huspenina, J., Weichert, W., Knapp, S., Feller, S Tags: Cancer, Pharmacology & Drug Discovery, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
