Stress-response balance drives the evolution of a network module and its host genome
Stress response genes and their regulators form networks that underlie drug resistance. These networks often have an inherent tradeoff: their expression is costly in the absence of stress, but beneficial in stress. They can quickly emerge in the genomes of infectious microbes and cancer cells, protecting them from treatment. Yet, the evolution of stress resistance networks is not well understood. Here, we use a two-component synthetic gene circuit integrated into the budding yeast genome to model experimentally the adaptation of a stress response module and its host genome in three different scenarios. In agreement with co...
Source: Molecular Systems Biology - August 31, 2015 Category: Molecular Biology Authors: Gonzalez, C., Ray, J. C. J., Manhart, M., Adams, R. M., Nevozhay, D., Morozov, A. V., Balazsi, G. Tags: Evolution, Quantitative Biology & Dynamical Systems, Synthetic Biology & Biotechnology Articles Source Type: research
Comprehensive assembly of novel transcripts from unmapped human RNA-Seq data and their association with cancer
Crucial parts of the genome including genes encoding microRNAs and noncoding RNAs went unnoticed for years, and even now, despite extensive annotation and assembly of the human genome, RNA-sequencing continues to yield millions of unmappable and thus uncharacterized reads. Here, we examined > 300 billion reads from 536 normal donors and 1,873 patients encompassing 21 cancer types, identified ~300 million such uncharacterized reads, and using a distinctive approach de novo assembled 2,550 novel human transcripts, which mainly represent long noncoding RNAs. Of these, 230 exhibited relatively specific expression ...
Source: Molecular Systems Biology - August 7, 2015 Category: Molecular Biology Authors: Kazemian, M., Ren, M., Lin, J.-X., Liao, W., Spolski, R., Leonard, W. J. Tags: Cancer, Chromatin, Epigenetics, Genomics & Functional Genomics Articles Source Type: research
Extensive allele-specific translational regulation in hybrid mice
Translational regulation is mediated through the interaction between diffusible trans-factors and cis-elements residing within mRNA transcripts. In contrast to extensively studied transcriptional regulation, cis-regulation on translation remains underexplored. Using deep sequencing-based transcriptome and polysome profiling, we globally profiled allele-specific translational efficiency for the first time in an F1 hybrid mouse. Out of 7,156 genes with reliable quantification of both alleles, we found 1,008 (14.1%) exhibiting significant allelic divergence in translational efficiency. Systematic analysis of sequence features...
Source: Molecular Systems Biology - August 7, 2015 Category: Molecular Biology Authors: Hou, J., Wang, X., McShane, E., Zauber, H., Sun, W., Selbach, M., Chen, W. Tags: Genome-Scale & Integrative Biology, Protein Biosynthesis & Quality Control Articles Source Type: research
Cancer type-dependent genetic interactions between cancer driver alterations indicate plasticity of epistasis across cell types
Cancers, like many diseases, are normally caused by combinations of genetic alterations rather than by changes affecting single genes. It is well established that the genetic alterations that drive cancer often interact epistatically, having greater or weaker consequences in combination than expected from their individual effects. In a stringent statistical analysis of data from > 3,000 tumors, we find that the co-occurrence and mutual exclusivity relationships between cancer driver alterations change quite extensively in different types of cancer. This cannot be accounted for by variation in tumor heterogeneity or...
Source: Molecular Systems Biology - July 30, 2015 Category: Molecular Biology Authors: Park, S., Lehner, B. Tags: Cancer, Genetics, Gene Therapy & Genetic Disease, Network Biology Articles Source Type: research
Isolated cell behavior drives the evolution of antibiotic resistance
Bacterial antibiotic resistance is typically quantified by the minimum inhibitory concentration (MIC), which is defined as the minimal concentration of antibiotic that inhibits bacterial growth starting from a standard cell density. However, when antibiotic resistance is mediated by degradation, the collective inactivation of antibiotic by the bacterial population can cause the measured MIC to depend strongly on the initial cell density. In cases where this inoculum effect is strong, the relationship between MIC and bacterial fitness in the antibiotic is not well defined. Here, we demonstrate that the resistance of a singl...
Source: Molecular Systems Biology - July 29, 2015 Category: Molecular Biology Authors: Artemova, T., Gerardin, Y., Dudley, C., Vega, N. M., Gore, J. Tags: Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems Articles Source Type: research
Structure of silent transcription intervals and noise characteristics of mammalian genes
Mammalian transcription occurs stochastically in short bursts interspersed by silent intervals showing a refractory period. However, the underlying processes and consequences on fluctuations in gene products are poorly understood. Here, we use single allele time-lapse recordings in mouse cells to identify minimal models of promoter cycles, which inform on the number and durations of rate-limiting steps responsible for refractory periods. The structure of promoter cycles is gene specific and independent of genomic location. Typically, five rate-limiting steps underlie the silent periods of endogenous promoters, while minima...
Source: Molecular Systems Biology - July 27, 2015 Category: Molecular Biology Authors: Zoller, B., Nicolas, D., Molina, N., Naef, F. Tags: Quantitative Biology & Dynamical Systems, Transcription Articles Source Type: research
Extensive mapping of an innate immune network with CRISPR
The application of the CRISPR-Cas9 system marks a major breakthrough for genetic screens, particularly in mammalian cells where high-throughput targeted gene editing has been lacking. Parnas et al (2015) apply this screening technology to mouse bone marrow-derived dendritic cells in order to study the regulation of the immune response triggered by PAMPs. Through integrated analysis of gene knockouts in conjunction with changes in protein and mRNA expression, CRISPR screens are facilitating dissection of immune regulatory networks at unprecedented resolution. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - July 24, 2015 Category: Molecular Biology Authors: Aregger, M., Hart, T., Moffat, J. Tags: Genome-Scale & Integrative Biology, Immunology News [amp ] Views Source Type: research
Genetic variation in insulin-induced kinase signaling
Individual differences in sensitivity to insulin contribute to disease susceptibility including diabetes and metabolic syndrome. Cellular responses to insulin are well studied. However, which steps in these response pathways differ across individuals remains largely unknown. Such knowledge is needed to guide more precise therapeutic interventions. Here, we studied insulin response and found extensive individual variation in the activation of key signaling factors, including ERK whose induction differs by more than 20-fold among our subjects. This variation in kinase activity is propagated to differences in downstream gene ...
Source: Molecular Systems Biology - July 22, 2015 Category: Molecular Biology Authors: Wang, I. X., Ramrattan, G., Cheung, V. G. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Signal Transduction Articles Source Type: research
Time- and compartment-resolved proteome profiling of the extracellular niche in lung injury and repair
The extracellular matrix (ECM) is a key regulator of tissue morphogenesis and repair. However, its composition and architecture are not well characterized. Here, we monitor remodeling of the extracellular niche in tissue repair in the bleomycin-induced lung injury mouse model. Mass spectrometry quantified 8,366 proteins from total tissue and bronchoalveolar lavage fluid (BALF) over the course of 8 weeks, surveying tissue composition from the onset of inflammation and fibrosis to its full recovery. Combined analysis of proteome, secretome, and transcriptome highlighted post-transcriptional events during tissue fib...
Source: Molecular Systems Biology - July 14, 2015 Category: Molecular Biology Authors: Schiller, H. B., Fernandez, I. E., Burgstaller, G., Schaab, C., Scheltema, R. A., Schwarzmayr, T., Strom, T. M., Eickelberg, O., Mann, M. Tags: Genome-Scale & Integrative Biology, Molecular Biology of Disease, Post-translational Modifications, Proteolysis & Proteomics Articles Source Type: research
Data-driven modelling of a gene regulatory network for cell fate decisions in the growing limb bud
Parameter optimization coupled with model selection is a convenient approach to infer gene regulatory networks from experimental gene expression data, but so far it has been limited to single cells or static tissues where growth is not significant. Here, we present a computational study in which we determine an optimal gene regulatory network from the spatiotemporal dynamics of gene expression patterns in a complex 2D growing tissue (non-isotropic and heterogeneous growth rates). We use this method to predict the regulatory mechanisms that underlie proximodistal (PD) patterning of the developing limb bud. First, we map the...
Source: Molecular Systems Biology - July 14, 2015 Category: Molecular Biology Authors: Uzkudun, M., Marcon, L., Sharpe, J. Tags: Development & Differentiation, Quantitative Biology & Dynamical Systems Articles Source Type: research
Pom1 gradient buffering through intermolecular auto-phosphorylation
Concentration gradients provide spatial information for tissue patterning and cell organization, and their robustness under natural fluctuations is an evolutionary advantage. In rod-shaped Schizosaccharomyces pombe cells, the DYRK-family kinase Pom1 gradients control cell division timing and placement. Upon dephosphorylation by a Tea4-phosphatase complex, Pom1 associates with the plasma membrane at cell poles, where it diffuses and detaches upon auto-phosphorylation. Here, we demonstrate that Pom1 auto-phosphorylates intermolecularly, both in vitro and in vivo, which confers robustness to the gradient. Quantitati...
Source: Molecular Systems Biology - July 6, 2015 Category: Molecular Biology Authors: Hersch, M., Hachet, O., Dalessi, S., Ullal, P., Bhatia, P., Bergmann, S., Martin, S. G. Tags: Quantitative Biology & Dynamical Systems, Signal Transduction Reports Source Type: research
Predominant contribution of cis-regulatory divergence in the evolution of mouse alternative splicing
Divergence of alternative splicing represents one of the major driving forces to shape phenotypic diversity during evolution. However, the extent to which these divergences could be explained by the evolving cis-regulatory versus trans-acting factors remains unresolved. To globally investigate the relative contributions of the two factors for the first time in mammals, we measured splicing difference between C57BL/6J and SPRET/EiJ mouse strains and allele-specific splicing pattern in their F1 hybrid. Out of 11,818 alternative splicing events expressed in the cultured fibroblast cells, we identified 796 with significant dif...
Source: Molecular Systems Biology - July 1, 2015 Category: Molecular Biology Authors: Gao, Q., Sun, W., Ballegeer, M., Libert, C., Chen, W. Tags: Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology, Transcription Articles Source Type: research
Modeling cancer metabolism on a genome scale
Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigenicity and malignancy. In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one of the hallmarks of cancer. Deciphering the full scope and functional implications of the dysregulated metabolism in cancer requires both the advancement of a variety of omics measurements and the advancement of computational approaches for the analysis and contextualization of the accumulated data. En...
Source: Molecular Systems Biology - June 30, 2015 Category: Molecular Biology Authors: Yizhak, K., Chaneton, B., Gottlieb, E., Ruppin, E. Tags: Computational Biology, Genome-Scale & Integrative Biology, Metabolism Reviews Source Type: research
Systems-level quantification of division timing reveals a common genetic architecture controlling asynchrony and fate asymmetry
Coordination of cell division timing is crucial for proper cell fate specification and tissue growth. However, the differential regulation of cell division timing across or within cell types during metazoan development remains poorly understood. To elucidate the systems-level genetic architecture coordinating division timing, we performed a high-content screening for genes whose depletion produced a significant reduction in the asynchrony of division between sister cells (ADS) compared to that of wild-type during Caenorhabditis elegans embryogenesis. We quantified division timing using 3D time-lapse imaging followed by com...
Source: Molecular Systems Biology - June 10, 2015 Category: Molecular Biology Authors: Ho, V. W. S., Wong, M.-K., An, X., Guan, D., Shao, J., Ng, H. C. K., Ren, X., He, K., Liao, J., Ang, Y., Chen, L., Huang, X., Yan, B., Xia, Y., Chan, L. L. H., Chow, K. L., Yan, H., Zhao, Z. Tags: Cell Cycle, Development & Differentiation, Methods & Resources Articles Source Type: research
Phosphoproteome dynamics of Saccharomyces cerevisiae under heat shock and cold stress
The ability of cells and organisms to survive and function through changes in temperature evolved from their specific adaptations to nonoptimal growth conditions. Responses to elevated temperatures have been studied in yeast and other model organisms using transcriptome profiling and provided valuable biological insights on molecular mechanisms involved in stress tolerance and adaptation to adverse environment. In contrast, little is known about rapid signaling events associated with changes in temperature. To gain a better understanding of global changes in protein phosphorylation in response to heat and cold, we develope...
Source: Molecular Systems Biology - June 3, 2015 Category: Molecular Biology Authors: Kanshin, E., Kubiniok, P., Thattikota, Y., D'Amours, D., Thibault, P. Tags: Genome-Scale & Integrative Biology, Post-translational Modifications, Proteolysis & Proteomics, Signal Transduction Articles Source Type: research
