Capturing protein communities by structural proteomics in a thermophilic eukaryote
The arrangement of proteins into complexes is a key organizational principle for many cellular functions. Although the topology of many complexes has been systematically analyzed in isolation, their molecular sociology in situ remains elusive. Here, we show that crude cellular extracts of a eukaryotic thermophile, Chaetomium thermophilum, retain basic principles of cellular organization. Using a structural proteomics approach, we simultaneously characterized the abundance, interactions, and structure of a third of the C. thermophilum proteome within these extracts. We identified 27 distinct protein communities th...
Source: Molecular Systems Biology - July 25, 2017 Category: Molecular Biology Authors: Kastritis, P. L., O'Reilly, F. J., Bock, T., Li, Y., Rogon, M. Z., Buczak, K., Romanov, N., Betts, M. J., Bui, K. H., Hagen, W. J., Hennrich, M. L., Mackmull, M.-T., Rappsilber, J., Russell, R. B., Bork, P., Beck, M., Gavin, A.-C. Tags: Metabolism, Post-translational Modifications, Proteolysis & Proteomics, Structural Biology Articles Source Type: research
Quantitative analysis of protein interaction network dynamics in yeast
Many cellular functions are mediated by protein–protein interaction networks, which are environment dependent. However, systematic measurement of interactions in diverse environments is required to better understand the relative importance of different mechanisms underlying network dynamics. To investigate environment-dependent protein complex dynamics, we used a DNA-barcode-based multiplexed protein interaction assay in Saccharomyces cerevisiae to measure in vivo abundance of 1,379 binary protein complexes under 14 environments. Many binary complexes (55%) were environment dependent, especially those involving ...
Source: Molecular Systems Biology - July 13, 2017 Category: Molecular Biology Authors: Celaj, A., Schlecht, U., Smith, J. D., Xu, W., Suresh, S., Miranda, M., Aparicio, A. M., Proctor, M., Davis, R. W., Roth, F. P., St.Onge, R. P. Tags: Genome-Scale & Integrative Biology, Methods & Resources, Network Biology Articles Source Type: research
Biphasic response as a mechanism against mutant takeover in tissue homeostasis circuits
Tissues use feedback circuits in which cells send signals to each other to control their growth and survival. We show that such feedback circuits are inherently unstable to mutants that misread the signal level: Mutants have a growth advantage to take over the tissue, and cannot be eliminated by known cell-intrinsic mechanisms. To resolve this, we propose that tissues have biphasic responses in and the signal is toxic at both high and low levels, such as glucotoxicity of beta cells, excitotoxicity in neurons, and toxicity of growth factors to T cells. This gives most of these mutants a frequency-dependent selective disadva...
Source: Molecular Systems Biology - June 26, 2017 Category: Molecular Biology Authors: Karin, O., Alon, U. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Integration of over 9,000 mass spectrometry experiments builds a global map of human protein complexes
Macromolecular protein complexes carry out many of the essential functions of cells, and many genetic diseases arise from disrupting the functions of such complexes. Currently, there is great interest in defining the complete set of human protein complexes, but recent published maps lack comprehensive coverage. Here, through the synthesis of over 9,000 published mass spectrometry experiments, we present hu.MAP, the most comprehensive and accurate human protein complex map to date, containing > 4,600 total complexes, > 7,700 proteins, and > 56,000 unique interactions, including thousands of confident...
Source: Molecular Systems Biology - June 8, 2017 Category: Molecular Biology Authors: Drew, K., Lee, C., Huizar, R. L., Tu, F., Borgeson, B., McWhite, C. D., Ma, Y., Wallingford, J. B., Marcotte, E. M. Tags: Genome-Scale & Integrative Biology, Network Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Alternative TSSs are co-regulated in single cells in the mouse brain
Alternative transcription start sites (TSSs) have been extensively studied genome-wide for many cell types and have been shown to be important during development and to regulate transcript abundance between cell types. Likewise, single-cell gene expression has been extensively studied for many cell types. However, how single cells use TSSs has not yet been examined. In particular, it is unknown whether alternative TSSs are independently expressed, or whether they are co-activated or even mutually exclusive in single cells. Here, we use a previously published single-cell RNA-seq dataset, comprising thousands of cells, to st...
Source: Molecular Systems Biology - May 11, 2017 Category: Molecular Biology Authors: Karlsson, K., Lönnerberg, P., Linnarsson, S. Tags: Genome-Scale & Integrative Biology, Transcription Articles Source Type: research
High-throughput CRISPRi phenotyping identifies new essential genes in Streptococcus pneumoniae
Genome-wide screens have discovered a large set of essential genes in the opportunistic human pathogen Streptococcus pneumoniae. However, the functions of many essential genes are still unknown, hampering vaccine development and drug discovery. Based on results from transposon sequencing (Tn-seq), we refined the list of essential genes in S. pneumoniae serotype 2 strain D39. Next, we created a knockdown library targeting 348 potentially essential genes by CRISPR interference (CRISPRi) and show a growth phenotype for 254 of them (73%). Using high-content microscopy screening, we searched for essential genes of unknown ...
Source: Molecular Systems Biology - May 10, 2017 Category: Molecular Biology Authors: Liu, X., Gallay, C., Kjos, M., Domenech, A., Slager, J., van Kessel, S. P., Knoops, K., Sorg, R. A., Zhang, J.-R., Veening, J.-W. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
An immediate-late gene expression module decodes ERK signal duration
The RAF-MEK-ERK signalling pathway controls fundamental, often opposing cellular processes such as proliferation and apoptosis. Signal duration has been identified to play a decisive role in these cell fate decisions. However, it remains unclear how the different early and late responding gene expression modules can discriminate short and long signals. We obtained both protein phosphorylation and gene expression time course data from HEK293 cells carrying an inducible construct of the proto-oncogene RAF. By mathematical modelling, we identified a new gene expression module of immediate–late genes (ILGs) distinct in g...
Source: Molecular Systems Biology - May 3, 2017 Category: Molecular Biology Authors: Uhlitz, F., Sieber, A., Wyler, E., Fritsche-Guenther, R., Meisig, J., Landthaler, M., Klinger, B., Blüthgen, N. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction, Transcription Articles Source Type: research
A Notch positive feedback in the intestinal stem cell niche is essential for stem cell self-renewal
This study highlights the importance of feedback mechanisms in spatiotemporal control of the stem cell niche. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - April 28, 2017 Category: Molecular Biology Authors: Chen, K.-Y., Srinivasan, T., Tung, K.-L., Belmonte, J. M., Wang, L., Murthy, P. K. L., Choi, J., Rakhilin, N., King, S., Varanko, A. K., Witherspoon, M., Nishimura, N., Glazier, J. A., Lipkin, S. M., Bu, P., Shen, X. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction, Stem Cells Articles Source Type: research
A spectrum of modularity in multi-functional gene circuits
A major challenge in systems biology is to understand the relationship between a circuit's structure and its function, but how is this relationship affected if the circuit must perform multiple distinct functions within the same organism? In particular, to what extent do multi-functional circuits contain modules which reflect the different functions? Here, we computationally survey a range of bi-functional circuits which show no simple structural modularity: They can switch between two qualitatively distinct functions, while both functions depend on all genes of the circuit. Our analysis reveals two distinct classes: hybri...
Source: Molecular Systems Biology - April 27, 2017 Category: Molecular Biology Authors: Jimenez, A., Cotterell, J., Munteanu, A., Sharpe, J. Tags: Network Biology, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Integrative genomics of gene and metabolic regulation by estrogen receptors {alpha} and {beta}, and their coregulators
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - April 25, 2017 Category: Molecular Biology Authors: Madak-Erdogan, Z., Charn, T.-H., Jiang, Y., Liu, E. T., Katzenellenbogen, J. A., Katzenellenbogen, B. S. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Metabolism Corrigendum Source Type: research
A photoconversion model for full spectral programming and multiplexing of optogenetic systems
Optogenetics combines externally applied light signals and genetically engineered photoreceptors to control cellular processes with unmatched precision. Here, we develop a mathematical model of wavelength- and intensity-dependent photoconversion, signaling, and output gene expression for our two previously engineered light-sensing Escherichia coli two-component systems. To parameterize the model, we develop a simple set of spectral and dynamical calibration experiments using our recent open-source "Light Plate Apparatus" device. In principle, the parameterized model should predict the gene expression response to any t...
Source: Molecular Systems Biology - April 24, 2017 Category: Molecular Biology Authors: Olson, E. J., Tzouanas, C. N., Tabor, J. J. Tags: Methods & Resources, Quantitative Biology & Dynamical Systems, Synthetic Biology & Biotechnology Articles Source Type: research
Automated analysis of high-content microscopy data with deep learning
This study highlights deep learning as an important tool for the expedited analysis of high-content microscopy data. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - April 18, 2017 Category: Molecular Biology Authors: Kraus, O. Z., Grys, B. T., Ba, J., Chong, Y., Frey, B. J., Boone, C., Andrews, B. J. Tags: Computational Biology, Methods & Resources Articles Source Type: research
Engineering bacterial thiosulfate and tetrathionate sensors for detecting gut inflammation
There is a groundswell of interest in using genetically engineered sensor bacteria to study gut microbiota pathways, and diagnose or treat associated diseases. Here, we computationally identify the first biological thiosulfate sensor and an improved tetrathionate sensor, both two-component systems from marine Shewanella species, and validate them in laboratory Escherichia coli. Then, we port these sensors into a gut-adapted probiotic E. coli strain, and develop a method based upon oral gavage and flow cytometry of colon and fecal samples to demonstrate that colon inflammation (colitis) activates the thiosulfate s...
Source: Molecular Systems Biology - April 3, 2017 Category: Molecular Biology Authors: Daeffler, K. N.-M., Galley, J. D., Sheth, R. U., Ortiz-Velez, L. C., Bibb, C. O., Shroyer, N. F., Britton, R. A., Tabor, J. J. Tags: Microbiology, Virology & Host Pathogen Interaction, Synthetic Biology & Biotechnology Articles Source Type: research
Proteomics and integrative omic approaches for understanding host-pathogen interactions and infectious diseases
Organisms are constantly exposed to microbial pathogens in their environments. When a pathogen meets its host, a series of intricate intracellular interactions shape the outcome of the infection. The understanding of these host–pathogen interactions is crucial for the development of treatments and preventive measures against infectious diseases. Over the past decade, proteomic approaches have become prime contributors to the discovery and understanding of host–pathogen interactions that represent anti- and pro-pathogenic cellular responses. Here, we review these proteomic methods and their application to studyi...
Source: Molecular Systems Biology - March 27, 2017 Category: Molecular Biology Authors: Jean Beltran, P. M., Federspiel, J. D., Sheng, X., Cristea, I. M. Tags: Genome-Scale & Integrative Biology, Microbiology, Virology & Host Pathogen Interaction, Post-translational Modifications, Proteolysis & Proteomics Reviews Source Type: research
Mechanism for microbial population collapse in a fluctuating resource environment
Managing trade-offs through gene regulation is believed to confer resilience to a microbial community in a fluctuating resource environment. To investigate this hypothesis, we imposed a fluctuating environment that required the sulfate-reducer Desulfovibrio vulgaris to undergo repeated ecologically relevant shifts between retaining metabolic independence (active capacity for sulfate respiration) and becoming metabolically specialized to a mutualistic association with the hydrogen-consuming Methanococcus maripaludis. Strikingly, the microbial community became progressively less proficient at restoring the environmentally re...
Source: Molecular Systems Biology - March 19, 2017 Category: Molecular Biology Authors: Turkarslan, S., Raman, A. V., Thompson, A. W., Arens, C. E., Gillespie, M. A., von Netzer, F., Hillesland, K. L., Stolyar, S., Lopez Garcia de Lomana, A., Reiss, D. J., Gorman-Lewis, D., Zane, G. M., Ranish, J. A., Wall, J. D., Stahl, D. A., Baliga, N. S. Tags: Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems Articles Source Type: research
