Molecular systems biology

Revealing a signaling role of phytosphingosine-1-phosphate in yeast.

Publication Date: 2010 PMID: 20160710
Authors: Cowart, L. A. - Shotwell, M. - Worley, M. L. - Richards, A. J. - Montefusco, D. J. - Hannun, Y. A. - Lu, X.
Journal: Mol Syst Biol

Sphingolipids including sphingosine-1-phosphate and ceramide participate in numerous cell programs through signaling mechanisms. This class of lipids has important functions in stress responses; however, determining which sphingolipid mediates specific events has remained encumbered by the numerous metabolic interconnections of sphingolipids, such that modulating a specific lipid of interest through manipulating metabolic enzymes causes 'ripple effects', which change levels of many other lipids. Here, we develop a method of integrative analysis for genomic, transcriptomic, and lipidomic data to address this previously intractable problem. This method revealed a specific signaling role for phytosphingosine-1-phosphate, a lipid with no previously defined specific function in yeast, in regulating genes required for mitochondrial respiration through the HAP complex transcription factor. This approach could be applied to extract meaningful biological information from a similar experimental design that produces multiple sets of high-throughput data.

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Intracellular transactivation of HIV can account for the decelerating decay of virus load during drug therapy.

Publication Date: 2010 PMID: 20160709
Authors: Althaus, C. L. - De Boer, R. J.
Journal: Mol Syst Biol

Basic virus dynamics models have been essential in understanding quantitative issues of HIV replication. However, several parts of the viral life cycle remain elusive. One of the most critical steps is the start of viral transcription, which is governed by the regulatory protein trans-activator of transcription (Tat) that induces a positive feedback loop. It has been shown that this feedback loop can alternate between two states leading to a transient activation of viral transcription. Using Monte Carlo simulations, we integrate the transactivation circuit into a new virus dynamics model having an age-dependent transactivation rate and reversion into latency. The cycling of infected cells between an activated and latent state results in the typical decelerating decay of virus load following therapy. Further, we hypothesize that the activation of latently infected cells is governed by the basal transcription rate of the integrated provirus rather than the intra- or extracellular environment. Finally, our systems approach to modeling virus dynamics offers a promising framework to infer the extracellular dynamics of cell populations from their intracellular reaction networks.

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Feedback between p21 and reactive oxygen production is necessary for cell senescence.

Publication Date: 2010 PMID: 20160708
Authors: Passos, J. F. - Nelson, G. - Wang, C. - Richter, T. - Simillion, C. - Proctor, C. J. - Miwa, S. - Olijslagers, S. - Hallinan, J. - Wipat, A. - Saretzki, G. - Rudolph, K. L. - Kirkwood, T. B. - von Zglinicki, T.
Journal: Mol Syst Biol

Cellular senescence--the permanent arrest of cycling in normally proliferating cells such as fibroblasts--contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFbeta. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

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Different sets of QTLs influence fitness variation in yeast.

Publication Date: 2010 PMID: 20160707
Authors: Romano, G. H. - Gurvich, Y. - Lavi, O. - Ulitsky, I. - Shamir, R. - Kupiec, M.
Journal: Mol Syst Biol

Most of the phenotypes in nature are complex and are determined by many quantitative trait loci (QTLs). In this study we identify gene sets that contribute to one important complex trait: the ability of yeast cells to survive under alkali stress. We carried out an in-lab evolution (ILE) experiment, in which we grew yeast populations under increasing alkali stress to enrich for beneficial mutations. The populations acquired different sets of affecting alleles, showing that evolution can provide alternative solutions to the same challenge. We measured the contribution of each allele to the phenotype. The sum of the effects of the QTLs was larger than the difference between the ancestor phenotype and the evolved strains, suggesting epistatic interactions between the QTLs. In parallel, a clinical isolated strain was used to map natural QTLs affecting growth at high pH. In all, 17 candidate regions were found. Using a predictive algorithm based on the distances in protein-interaction networks, candidate genes were defined and validated by gene disruption. Many of the QTLs found by both methods are not directly implied in pH homeostasis but have more general, and often regulatory, roles.

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