Chemogenomics and orthology-based design of antibiotic combination therapies
Combination antibiotic therapies are being increasingly used in the clinic to enhance potency and counter drug resistance. However, the large search space of candidate drugs and dosage regimes makes the identification of effective combinations highly challenging. Here, we present a computational approach called INDIGO, which uses chemogenomics data to predict antibiotic combinations that interact synergistically or antagonistically in inhibiting bacterial growth. INDIGO quantifies the influence of individual chemical–genetic interactions on synergy and antagonism and significantly outperforms existing approaches base...
Source: Molecular Systems Biology - May 23, 2016 Category: Molecular Biology Authors: Chandrasekaran, S., Cokol-Cakmak, M., Sahin, N., Yilancioglu, K., Kazan, H., Collins, J. J., Cokol, M. Tags: Genome-Scale & Integrative Biology, Methods & Resources, Pharmacology & Drug Discovery Articles Source Type: research
Slowdown of growth controls cellular differentiation
How can changes in growth rate affect the regulatory networks behavior and the outcomes of cellular differentiation? We address this question by focusing on starvation response in sporulating Bacillus subtilis. We show that the activity of sporulation master regulator Spo0A increases with decreasing cellular growth rate. Using a mathematical model of the phosphorelay—the network controlling Spo0A—we predict that this increase in Spo0A activity can be explained by the phosphorelay protein accumulation and lengthening of the period between chromosomal replication events caused by growth slowdown. As a result, onl...
Source: Molecular Systems Biology - May 22, 2016 Category: Molecular Biology Authors: Narula, J., Kuchina, A., Zhang, F., Fujita, M., Süel, G. M., Igoshin, O. A. Tags: Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems Articles Source Type: research
Translation elicits a growth rate-dependent, genome-wide, differential protein production in Bacillus subtilis
Complex regulatory programs control cell adaptation to environmental changes by setting condition-specific proteomes. In balanced growth, bacterial protein abundances depend on the dilution rate, transcript abundances and transcript-specific translation efficiencies. We revisited the current theory claiming the invariance of bacterial translation efficiency. By integrating genome-wide transcriptome datasets and datasets from a library of synthetic gfp-reporter fusions, we demonstrated that translation efficiencies in Bacillus subtilis decreased up to fourfold from slow to fast growth. The translation initiation regions eli...
Source: Molecular Systems Biology - May 16, 2016 Category: Molecular Biology Authors: Borkowski, O., Goelzer, A., Schaffer, M., Calabre, M., Mäder, U., Aymerich, S., Jules, M., Fromion, V. Tags: Genome-Scale & Integrative Biology, Protein Biosynthesis & Quality Control, Quantitative Biology & Dynamical Systems Articles Source Type: research
A population-based temporal logic gate for timing and recording chemical events
Engineered bacterial sensors have potential applications in human health monitoring, environmental chemical detection, and materials biosynthesis. While such bacterial devices have long been engineered to differentiate between combinations of inputs, their potential to process signal timing and duration has been overlooked. In this work, we present a two-input temporal logic gate that can sense and record the order of the inputs, the timing between inputs, and the duration of input pulses. Our temporal logic gate design relies on unidirectional DNA recombination mediated by bacteriophage integrases to detect and encode seq...
Source: Molecular Systems Biology - May 16, 2016 Category: Molecular Biology Authors: Hsiao, V., Hori, Y., Rothemund, P. W., Murray, R. M. Tags: Quantitative Biology & Dynamical Systems, Synthetic Biology & Biotechnology Articles Source Type: research
Tristetraprolin binding site atlas in the macrophage transcriptome reveals a switch for inflammation resolution
Precise regulation of mRNA decay is fundamental for robust yet not exaggerated inflammatory responses to pathogens. However, a global model integrating regulation and functional consequences of inflammation-associated mRNA decay remains to be established. Using time-resolved high-resolution RNA binding analysis of the mRNA-destabilizing protein tristetraprolin (TTP), an inflammation-limiting factor, we qualitatively and quantitatively characterize TTP binding positions in the transcriptome of immunostimulated macrophages. We identify pervasive destabilizing and non-destabilizing TTP binding, including a robust intronic bin...
Source: Molecular Systems Biology - May 12, 2016 Category: Molecular Biology Authors: Sedlyarov, V., Fallmann, J., Ebner, F., Huemer, J., Sneezum, L., Ivin, M., Kreiner, K., Tanzer, A., Vogl, C., Hofacker, I., Kovarik, P. Tags: Genome-Scale & Integrative Biology, Methods & Resources, RNA Biology Articles Source Type: research
Sensing a revolution
New fully integrated biosensors that monitor molecular and physiological parameters throughout our bodies are set to revolutionize medicine and personalized healthcare. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - April 25, 2016 Category: Molecular Biology Authors: Steinmetz, L. M., Jones, A. Tags: Systems Medicine Editorial Source Type: research
Frequency modulation of ERK activation dynamics rewires cell fate
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - April 21, 2016 Category: Molecular Biology Authors: Ryu, H., Chung, M., Dobrzynski, M., Fey, D., Blum, Y., Sik Lee, S., Peter, M., Kholodenko, B. N., Li Jeon, N., Pertz, O. Tags: Corrigendum Source Type: research
An inter-species protein-protein interaction network across vast evolutionary distance
In cellular systems, biophysical interactions between macromolecules underlie a complex web of functional interactions. How biophysical and functional networks are coordinated, whether all biophysical interactions correspond to functional interactions, and how such biophysical-versus-functional network coordination is shaped by evolutionary forces are all largely unanswered questions. Here, we investigate these questions using an "inter-interactome" approach. We systematically probed the yeast and human proteomes for interactions between proteins from these two species and functionally characterized the resulting inter-int...
Source: Molecular Systems Biology - April 21, 2016 Category: Molecular Biology Authors: Zhong, Q., Pevzner, S. J., Hao, T., Wang, Y., Mosca, R., Menche, J., Taipale, M., Tasan, M., Fan, C., Yang, X., Haley, P., Murray, R. R., Mer, F., Gebreab, F., Tam, S., MacWilliams, A., Dricot, A., Reichert, P., Santhanam, B., Ghamsari, L., Calderwood, M. Tags: Evolution, Genome-Scale & Integrative Biology, Network Biology Articles Source Type: research
Predictive features of ligand-specific signaling through the estrogen receptor
Some estrogen receptor-α (ERα)-targeted breast cancer therapies such as tamoxifen have tissue-selective or cell-specific activities, while others have similar activities in different cell types. To identify biophysical determinants of cell-specific signaling and breast cancer cell proliferation, we synthesized 241 ERα ligands based on 19 chemical scaffolds, and compared ligand response using quantitative bioassays for canonical ERα activities and X-ray crystallography. Ligands that regulate the dynamics and stability of the coactivator-binding site in the C-terminal ligand-binding domain, called act...
Source: Molecular Systems Biology - April 21, 2016 Category: Molecular Biology Authors: Nwachukwu, J. C., Srinivasan, S., Zheng, Y., Wang, S., Min, J., Dong, C., Liao, Z., Nowak, J., Wright, N. J., Houtman, R., Carlson, K. E., Josan, J. S., Elemento, O., Katzenellenbogen, J. A., Zhou, H.-B., Nettles, K. W. Tags: Chemical Biology, Structural Biology, Transcription Articles Source Type: research
Pooled-matrix protein interaction screens using Barcode Fusion Genetics
High-throughput binary protein interaction mapping is continuing to extend our understanding of cellular function and disease mechanisms. However, we remain one or two orders of magnitude away from a complete interaction map for humans and other major model organisms. Completion will require screening at substantially larger scales with many complementary assays, requiring further efficiency gains in proteome-scale interaction mapping. Here, we report Barcode Fusion Genetics-Yeast Two-Hybrid (BFG-Y2H), by which a full matrix of protein pairs can be screened in a single multiplexed strain pool. BFG-Y2H uses Cre recombinatio...
Source: Molecular Systems Biology - April 21, 2016 Category: Molecular Biology Authors: Yachie, N., Petsalaki, E., Mellor, J. C., Weile, J., Jacob, Y., Verby, M., Ozturk, S. B., Li, S., Cote, A. G., Mosca, R., Knapp, J. J., Ko, M., Yu, A., Gebbia, M., Sahni, N., Yi, S., Tyagi, T., Sheykhkarimli, D., Roth, J. F., Wong, C., Musa, L., Snider, J Tags: Methods & Resources, Network Biology Articles Source Type: research
Transcriptomics resources of human tissues and organs
Quantifying the differential expression of genes in various human organs, tissues, and cell types is vital to understand human physiology and disease. Recently, several large-scale transcriptomics studies have analyzed the expression of protein-coding genes across tissues. These datasets provide a framework for defining the molecular constituents of the human body as well as for generating comprehensive lists of proteins expressed across tissues or in a tissue-restricted manner. Here, we review publicly available human transcriptome resources and discuss body-wide data from independent genome-wide transcriptome analyses of...
Source: Molecular Systems Biology - April 3, 2016 Category: Molecular Biology Authors: Uhlen, M., Hallström, B. M., Lindskog, C., Mardinoglu, A., Ponten, F., Nielsen, J. Tags: Genome-Scale & Integrative Biology, Metabolism, Methods & Resources Reviews Source Type: research
Environment-induced epigenetic reprogramming in genomic regulatory elements in smoking mothers and their children
Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype-related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular "commuting" enhancers having multiple, regulator...
Source: Molecular Systems Biology - March 23, 2016 Category: Molecular Biology Authors: Bauer, T., Trump, S., Ishaque, N., Thürmann, L., Gu, L., Bauer, M., Bieg, M., Gu, Z., Weichenhan, D., Mallm, J.-P., Röder, S., Herberth, G., Takada, E., Mücke, O., Winter, M., Junge, K. M., Grützmann, K., Rolle-Kampczyk, U. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Systems Medicine Articles Source Type: research
Integrative analyses reveal signaling pathways underlying familial breast cancer susceptibility
In this study, we performed integrated analyses of gene expression and exome-sequencing data from peripheral blood mononuclear cells and showed that cell adhesion pathways are significantly and consistently dysregulated in women who develop FBC. The dysregulation of cell adhesion pathways in high-risk women was also identified by pathway-based profiling applied to normal breast tissue data from two independent cohorts. The results of our genomic analyses were validated in normal primary mammary epithelial cells from high-risk and control women, using cell-based functional assays, drug-response assays, fluorescence microsco...
Source: Molecular Systems Biology - March 9, 2016 Category: Molecular Biology Authors: Piccolo, S. R., Hoffman, L. M., Conner, T., Shrestha, G., Cohen, A. L., Marks, J. R., Neumayer, L. A., Agarwal, C. A., Beckerle, M. C., Andrulis, I. L., Spira, A. E., Moos, P. J., Buys, S. S., Johnson, W. E., Bild, A. H. Tags: Cancer, Genome-Scale & Integrative Biology Articles Source Type: research
Coupling spatial segregation with synthetic circuits to control bacterial survival
Engineered bacteria have great potential for medical and environmental applications. Fulfilling this potential requires controllability over engineered behaviors and scalability of the engineered systems. Here, we present a platform technology, microbial swarmbot, which employs spatial arrangement to control the growth dynamics of engineered bacteria. As a proof of principle, we demonstrated a safeguard strategy to prevent unintended bacterial proliferation. In particular, we adopted several synthetic gene circuits to program collective survival in Escherichia coli: the engineered bacteria could only survive when present a...
Source: Molecular Systems Biology - February 29, 2016 Category: Molecular Biology Authors: Huang, S., Lee, A. J., Tsoi, R., Wu, F., Zhang, Y., Leong, K. W., You, L. Tags: Quantitative Biology & Dynamical Systems, Synthetic Biology & Biotechnology Articles Source Type: research
Positional proteomics reveals differences in N-terminal proteoform stability
To understand the impact of alternative translation initiation on a proteome, we performed a proteome-wide study on protein turnover using positional proteomics and ribosome profiling to distinguish between N-terminal proteoforms of individual genes. By combining pulsed SILAC with N-terminal COFRADIC, we monitored the stability of 1,941 human N-terminal proteoforms, including 147 N-terminal proteoform pairs that originate from alternative translation initiation, alternative splicing or incomplete processing of the initiator methionine. N-terminally truncated proteoforms were less abundant than canonical proteoforms an...
Source: Molecular Systems Biology - February 18, 2016 Category: Molecular Biology Authors: Gawron, D., Ndah, E., Gevaert, K., Van Damme, P. Tags: Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
