Molecular systems biology

Transcriptional regulation is only half the story.

Publication Date: 2010 Aug 24 PMID: 20739928
Authors: Plotkin, J. B.
Journal: Mol Syst Biol

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A model of yeast cell-cycle regulation based on multisite phosphorylation.

Publication Date: 2010 Aug 24 PMID: 20739927
Authors: Barik, D. - Baumann, W. T. - Paul, M. R. - Novak, B. - Tyson, J. J.
Journal: Mol Syst Biol

In order for the cell's genome to be passed intact from one generation to the next, the events of the cell cycle (DNA replication, mitosis, cell division) must be executed in the correct order, despite the considerable molecular noise inherent in any protein-based regulatory system residing in the small confines of a eukaryotic cell. To assess the effects of molecular fluctuations on cell-cycle progression in budding yeast cells, we have constructed a new model of the regulation of Cln- and Clb-dependent kinases, based on multisite phosphorylation of their target proteins and on positive and negative feedback loops involving the kinases themselves. To account for the significant role of noise in the transcription and translation steps of gene expression, the model includes mRNAs as well as proteins. The model equations are simulated deterministically and stochastically to reveal the bistable switching behavior on which proper cell-cycle progression depends and to show that this behavior is robust to the level of molecular noise expected in yeast-sized cells (approximately 50 fL volume). The model gives a quantitatively accurate account of the variability observed in the G1-S transition in budding yeast, which is governed by an underlying sizer+timer control system.

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Modeling genome-wide replication kinetics reveals a mechanism for regulation of replication timing.

Publication Date: 2010 Aug 24 PMID: 20739926
Authors: Yang, S. C. - Rhind, N. - Bechhoefer, J.
Journal: Mol Syst Biol

Microarrays are powerful tools to probe genome-wide replication kinetics. The rich data sets that result contain more information than has been extracted by current methods of analysis. In this paper, we present an analytical model that incorporates probabilistic initiation of origins and passive replication. Using the model, we performed least-squares fits to a set of recently published time course microarray data on Saccharomyces cerevisiae. We extracted the distribution of firing times for each origin and found that the later an origin fires on average, the greater the variation in firing times. To explain this trend, we propose a model where earlier-firing origins have more initiator complexes loaded and a more accessible chromatin environment. The model demonstrates how initiation can be stochastic and yet occur at defined times during S phase, without an explicit timing program. Furthermore, we hypothesize that the initiators in this model correspond to loaded minichromosome maintenance complexes. This model is the first to suggest a detailed, testable, biochemically plausible mechanism for the regulation of replication timing in eukaryotes.

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Structured digital tables on the Semantic Web: toward a structured digital literature.

Publication Date: 2010 Aug 24 PMID: 20739925
Authors: Cheung, K. H. - Samwald, M. - Auerbach, R. K. - Gerstein, M. B.
Journal: Mol Syst Biol

In parallel to the growth in bioscience databases, biomedical publications have increased exponentially in the past decade. However, the extraction of high-quality information from the corpus of scientific literature has been hampered by the lack of machine-interpretable content, despite text-mining advances. To address this, we propose creating a structured digital table as part of an overall effort in developing machine-readable, structured digital literature. In particular, we envision transforming publication tables into standardized triples using Semantic Web approaches. We identify three canonical types of tables (conveying information about properties, networks, and concept hierarchies) and show how more complex tables can be built from these basic types. We envision that authors would create tables initially using the structured triples for canonical types and then have them visually rendered for publication, and we present examples for converting representative tables into triples. Finally, we discuss how 'stub' versions of structured digital tables could be a useful bridge for connecting together the literature with databases, allowing the former to more precisely document the later.

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microRNA-122 as a regulator of mitochondrial metabolic gene network in hepatocellular carcinoma.

Publication Date: 2010 Aug 24 PMID: 20739924
Authors: Burchard, J. - Zhang, C. - Liu, A. M. - Poon, R. T. - Lee, N. P. - Wong, K. F. - Sham, P. C. - Lam, B. Y. - Ferguson, M. D. - Tokiwa, G. - Smith, R. - Leeson, B. - Beard, R. - Lamb, J. R. - Lim, L. - Mao, M. - Dai, H. - Luk, J. M.
Journal: Mol Syst Biol

Tumorigenesis involves multistep genetic alterations. To elucidate the microRNA (miRNA)-gene interaction network in carcinogenesis, we examined their genome-wide expression profiles in 96 pairs of tumor/non-tumor tissues from hepatocellular carcinoma (HCC). Comprehensive analysis of the coordinate expression of miRNAs and mRNAs reveals that miR-122 is under-expressed in HCC and that increased expression of miR-122 seed-matched genes leads to a loss of mitochondrial metabolic function. Furthermore, the miR-122 secondary targets, which decrease in expression, are good prognostic markers for HCC. Transcriptome profiling data from additional 180 HCC and 40 liver cirrhotic patients in the same cohort were used to confirm the anti-correlation of miR-122 primary and secondary target gene sets. The HCC findings can be recapitulated in mouse liver by silencing miR-122 with antagomir treatment followed by gene-expression microarray analysis. In vitro miR-122 data further provided a direct link between induction of miR-122-controlled genes and impairment of mitochondrial metabolism. In conclusion, miR-122 regulates mitochondrial metabolism and its loss may be detrimental to sustaining critical liver function and contribute to morbidity and mortality of liver cancer patients.

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Sequence signatures and mRNA concentration can explain two-thirds of protein abundance variation in a human cell line.

Publication Date: 2010 Aug 24 PMID: 20739923
Authors: Vogel, C. - Abreu Rde, S. - Ko, D. - Le, S. Y. - Shapiro, B. A. - Burns, S. C. - Sandhu, D. - Boutz, D. R. - Marcotte, E. M. - Penalva, L. O.
Journal: Mol Syst Biol

Transcription, mRNA decay, translation and protein degradation are essential processes during eukaryotic gene expression, but their relative global contributions to steady-state protein concentrations in multi-cellular eukaryotes are largely unknown. Using measurements of absolute protein and mRNA abundances in cellular lysate from the human Daoy medulloblastoma cell line, we quantitatively evaluate the impact of mRNA concentration and sequence features implicated in translation and protein degradation on protein expression. Sequence features related to translation and protein degradation have an impact similar to that of mRNA abundance, and their combined contribution explains two-thirds of protein abundance variation. mRNA sequence lengths, amino-acid properties, upstream open reading frames and secondary structures in the 5' untranslated region (UTR) were the strongest individual correlates of protein concentrations. In a combined model, characteristics of the coding region and the 3'UTR explained a larger proportion of protein abundance variation than characteristics of the 5'UTR. The absolute protein and mRNA concentration measurements for >1000 human genes described here represent one of the largest datasets currently available, and reveal both general trends and specific examples of post-transcriptional regulation.

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DamID in C. elegans reveals longevity-associated targets of DAF-16/FoxO.

Publication Date: 2010 Aug 10 PMID: 20706209
Authors: Schuster, E. - McElwee, J. J. - Tullet, J. M. - Doonan, R. - Matthijssens, F. - Reece-Hoyes, J. S. - Hope, I. A. - Vanfleteren, J. R. - Thornton, J. M. - Gems, D.
Journal: Mol Syst Biol

Insulin/IGF-1 signaling controls metabolism, stress resistance and aging in Caenorhabditis elegans by regulating the activity of the DAF-16/FoxO transcription factor (TF). However, the function of DAF-16 and the topology of the transcriptional network that it crowns remain unclear. Using chromatin profiling by DNA adenine methyltransferase identification (DamID), we identified 907 genes that are bound by DAF-16. These were enriched for genes showing DAF-16-dependent upregulation in long-lived daf-2 insulin/IGF-1 receptor mutants (P=1.4e(-11)). Cross-referencing DAF-16 targets with these upregulated genes (daf-2 versus daf-16; daf-2) identified 65 genes that were DAF-16 regulatory targets. These 65 were enriched for signaling genes, including known determinants of longevity, but not for genes specifying somatic maintenance functions (e.g. detoxification, repair). This suggests that DAF-16 acts within a relatively small transcriptional subnetwork activating (but not suppressing) other regulators of stress resistance and aging, rather than directly regulating terminal effectors of longevity. For most genes bound by DAF-16::DAM, transcriptional regulation by DAF-16 was not detected, perhaps reflecting transcriptionally non-functional TF 'parking sites'. This study demonstrates the efficacy of DamID for chromatin profiling in C. elegans.

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Cooperation and Hamilton's rule in a simple synthetic microbial system.

Publication Date: 2010 Aug 10 PMID: 20706208
Authors: Chuang, J. S. - Rivoire, O. - Leibler, S.
Journal: Mol Syst Biol

A fundamental problem in biology is understanding the evolutionary emergence and maintenance of altruistic behaviors. A well-recognized conceptual insight is provided by a general mathematical relation, Hamilton's rule. This rule can in principle be invoked to explain natural examples of cooperation, but measuring the variables that it involves is a particularly challenging problem and controlling these variables experimentally an even more daunting task. Here, we overcome these difficulties by using a simple synthetic microbial system of producers and nonproducers of an extracellular growth-enhancing molecule, which acts as a 'common good.' For this system, we are able to manipulate the intrinsic growth difference between producers and nonproducers, as well as the impact of the common good on the growth rate of its recipients. Our synthetic system is thus uniquely suited for studying the relation between the parameters entering Hamilton's rule and the quantities governing the systems' behavior. The experimental results highlight a crucial effect of nonlinearities in the response to the common good, which in general tend to limit the predictive value of Hamilton's rule.

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Targeted interactomics reveals a complex core cell cycle machinery in Arabidopsis thaliana.

Publication Date: 2010 Aug 10 PMID: 20706207
Authors: Van Leene, J. - Hollunder, J. - Eeckhout, D. - Persiau, G. - Van De Slijke, E. - Stals, H. - Van Isterdael, G. - Verkest, A. - Neirynck, S. - Buffel, Y. - De Bodt, S. - Maere, S. - Laukens, K. - Pharazyn, A. - Ferreira, P. C. - Eloy, N. - Renne, C. - Meyer, C. - Faure, J. D. - Steinbrenner, J. - Beynon, J. - Larkin, J. C. - Van de Peer, Y. - Hilson, P. - Kuiper, M. - De Veylder, L. - Van Onckelen, H. - Inze, D. - Witters, E. - De Jaeger, G.
Journal: Mol Syst Biol

Cell proliferation is the main driving force for plant growth. Although genome sequence analysis revealed a high number of cell cycle genes in plants, little is known about the molecular complexes steering cell division. In a targeted proteomics approach, we mapped the core complex machinery at the heart of the Arabidopsis thaliana cell cycle control. Besides a central regulatory network of core complexes, we distinguished a peripheral network that links the core machinery to up- and downstream pathways. Over 100 new candidate cell cycle proteins were predicted and an in-depth biological interpretation demonstrated the hypothesis-generating power of the interaction data. The data set provided a comprehensive view on heterodimeric cyclin-dependent kinase (CDK)-cyclin complexes in plants. For the first time, inhibitory proteins of plant-specific B-type CDKs were discovered and the anaphase-promoting complex was characterized and extended. Important conclusions were that mitotic A- and B-type cyclins form complexes with the plant-specific B-type CDKs and not with CDKA;1, and that D-type cyclins and S-phase-specific A-type cyclins seem to be associated exclusively with CDKA;1. Furthermore, we could show that plants have evolved a combinatorial toolkit consisting of at least 92 different CDK-cyclin complex variants, which strongly underscores the functional diversification among the large family of cyclins and reflects the pivotal role of cell cycle regulation in the developmental plasticity of plants.

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