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      Identification of the Proliferation/Differentiation Switch in the Cellular Network of Multicellular Organisms

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          Abstract

          The protein–protein interaction networks, or interactome networks, have been shown to have dynamic modular structures, yet the functional connections between and among the modules are less well understood. Here, using a new pipeline to integrate the interactome and the transcriptome, we identified a pair of transcriptionally anticorrelated modules, each consisting of hundreds of genes in multicellular interactome networks across different individuals and populations. The two modules are associated with cellular proliferation and differentiation, respectively. The proliferation module is conserved among eukaryotic organisms, whereas the differentiation module is specific to multicellular organisms. Upon differentiation of various tissues and cell lines from different organisms, the expression of the proliferation module is more uniformly suppressed, while the differentiation module is upregulated in a tissue- and species-specific manner. Our results indicate that even at the tissue and organism levels, proliferation and differentiation modules may correspond to two alternative states of the molecular network and may reflect a universal symbiotic relationship in a multicellular organism. Our analyses further predict that the proteins mediating the interactions between these modules may serve as modulators at the proliferation/differentiation switch.

          Synopsis

          Coordination of proliferation and differentiation is a fundamental process of multicellular organisms. Although at the cellular level proliferation and differentiation seem to correspond to different cellular states that can sometimes be seen separated by the proliferation/differentiation temporal switch, it is unclear whether such switch-like property exists at the tissue or organism level or whether it exists in postmitotic tissues in adult animals. Through integrating protein–protein interaction networks with gene expression profiles, Xia, Xue, Dong, Zhu, and colleagues found that a switch temporally separating proliferation- and differentiation-associated modules can also be detected in the adult human brain and the adult whole fruit fly. The expressions of the two modules are well coordinated at the system level. The evolutionary origins of the proliferation and differentiation modules further implicate a symbiotic relationship between the two modules. Network topologies and gene annotations support a regulatory role of the protein–protein interaction interface between the two modules.

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          Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing

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            Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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              A system of cluster analysis for genome-wide expression data from DNA microarray hybridization is described that uses standard statistical algorithms to arrange genes according to similarity in pattern of gene expression. The output is displayed graphically, conveying the clustering and the underlying expression data simultaneously in a form intuitive for biologists. We have found in the budding yeast Saccharomyces cerevisiae that clustering gene expression data groups together efficiently genes of known similar function, and we find a similar tendency in human data. Thus patterns seen in genome-wide expression experiments can be interpreted as indications of the status of cellular processes. Also, coexpression of genes of known function with poorly characterized or novel genes may provide a simple means of gaining leads to the functions of many genes for which information is not available currently.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                pcbi
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                November 2006
                24 November 2006
                : 2
                : 11
                : e145
                Affiliations
                [1 ] The Chinese Academy of Sciences Key Laboratory of Developmental Biology, Center for Molecular Systems Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, People's Republic of China
                [2 ] The State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, People's Republic of China
                Weill Medical College of Cornell University, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: jdhan@ 123456genetics.ac.cn
                Article
                06-PLCB-RA-0178R2 plcb-02-11-16
                10.1371/journal.pcbi.0020145
                1664705
                17166053
                9aeb1391-e825-4b76-b3d6-66e4815a15fc
                Copyright: © 2006 Xia 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.
                History
                : 8 May 2006
                : 21 September 2006
                Page count
                Pages: 16
                Categories
                Research Article
                Bioinformatics - Computational Biology
                Cell Biology
                Development
                Systems Biology
                Proliferation
                Differentiation
                Module
                Cellular Network
                Gene Expression
                Custom metadata
                Xia K, Xue H, Dong D, Zhu S, Wang J, et al. (2006) Identification of the proliferation/differentiation switch in the cellular network of multicellular organisms. PLoS Comput Biol 2(11): e145. doi: 10.1371/journal.pcbi.0020145

                Quantitative & Systems biology
                Quantitative & Systems biology

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