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Dynamic Changes in Protein Functional Linkage Networks Revealed by Integration with Gene Expression Data

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PLoS Computational Biology

Public Library of Science

2580820

10.1371/journal.pcbi.1000237

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      Abstract

      Response of cells to changing environmental conditions is governed by the dynamics of intricate biomolecular interactions. It may be reasonable to assume, proteins being the dominant macromolecules that carry out routine cellular functions, that understanding the dynamics of protein∶protein interactions might yield useful insights into the cellular responses. The large-scale protein interaction data sets are, however, unable to capture the changes in the profile of protein∶protein interactions. In order to understand how these interactions change dynamically, we have constructed conditional protein linkages for Escherichia coli by integrating functional linkages and gene expression information. As a case study, we have chosen to analyze UV exposure in wild-type and SOS deficient E. coli at 20 minutes post irradiation. The conditional networks exhibit similar topological properties. Although the global topological properties of the networks are similar, many subtle local changes are observed, which are suggestive of the cellular response to the perturbations. Some such changes correspond to differences in the path lengths among the nodes of carbohydrate metabolism correlating with its loss in efficiency in the UV treated cells. Similarly, expression of hubs under unique conditions reflects the importance of these genes. Various centrality measures applied to the networks indicate increased importance for replication, repair, and other stress proteins for the cells under UV treatment, as anticipated. We thus propose a novel approach for studying an organism at the systems level by integrating genome-wide functional linkages and the gene expression data.

      Author Summary

      Many cellular processes and the response of cells to environmental cues are determined by the intricate protein∶protein interactions. These cellular protein interactions can be represented in the form of a graph, where the nodes represent the proteins and the edges signify the interactions between them. However, the available protein functional linkage maps do not incorporate the dynamics of gene expression and thus do not portray the dynamics of true protein∶protein interactions in vivo. We have used gene expression data as well as the available protein functional interaction information for Escherichia coli to build the protein interaction networks for expressed genes in a given condition. These networks, named conditional networks, capture the differences in the protein interaction networks and hence the cell physiology. Thus, by exploring the dynamics of protein interaction profiles, we hope to understand the response of cells to environmental changes.

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      Most cited references 40

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      Cytoscape: a software environment for integrated models of biomolecular interaction networks.

      Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.
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        KEGG: kyoto encyclopedia of genes and genomes.

         S. Goto,  M Kanehisa (2000)
        KEGG (Kyoto Encyclopedia of Genes and Genomes) is a knowledge base for systematic analysis of gene functions, linking genomic information with higher order functional information. The genomic information is stored in the GENES database, which is a collection of gene catalogs for all the completely sequenced genomes and some partial genomes with up-to-date annotation of gene functions. The higher order functional information is stored in the PATHWAY database, which contains graphical representations of cellular processes, such as metabolism, membrane transport, signal transduction and cell cycle. The PATHWAY database is supplemented by a set of ortholog group tables for the information about conserved subpathways (pathway motifs), which are often encoded by positionally coupled genes on the chromosome and which are especially useful in predicting gene functions. A third database in KEGG is LIGAND for the information about chemical compounds, enzyme molecules and enzymatic reactions. KEGG provides Java graphics tools for browsing genome maps, comparing two genome maps and manipulating expression maps, as well as computational tools for sequence comparison, graph comparison and path computation. The KEGG databases are daily updated and made freely available (http://www. genome.ad.jp/kegg/).
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          Stochastic gene expression in a single cell.

          Clonal populations of cells exhibit substantial phenotypic variation. Such heterogeneity can be essential for many biological processes and is conjectured to arise from stochasticity, or noise, in gene expression. We constructed strains of Escherichia coli that enable detection of noise and discrimination between the two mechanisms by which it is generated. Both stochasticity inherent in the biochemical process of gene expression (intrinsic noise) and fluctuations in other cellular components (extrinsic noise) contribute substantially to overall variation. Transcription rate, regulatory dynamics, and genetic factors control the amplitude of noise. These results establish a quantitative foundation for modeling noise in genetic networks and reveal how low intracellular copy numbers of molecules can fundamentally limit the precision of gene regulation.
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            Author and article information

            Affiliations
            Centre for DNA Fingerprinting and Diagnostics, Nacharam, Hyderabad, India
            Peking University, China
            Author notes

            Conceived and designed the experiments: SRH. Performed the experiments: SRH. Analyzed the data: SRH PM SCM. Contributed reagents/materials/analysis tools: SRH PM. Wrote the paper: SRH PM SCM.

            Contributors
            Role: Editor
            Journal
            PLoS Comput Biol
            plos
            ploscomp
            PLoS Computational Biology
            Public Library of Science (San Francisco, USA)
            1553-734X
            1553-7358
            November 2008
            November 2008
            28 November 2008
            : 4
            : 11
            Luhua Lai (Editor)
            Hegde et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 9
            Categories
            Research Article
            Computational Biology/Genomics
            Computational Biology/Systems Biology
            ScienceOpen disciplines:

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