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Genome-wide deletion mutant analysis reveals genes required for respiratory growth, mitochondrial genome maintenance and mitochondrial protein synthesis in Saccharomyces cerevisiae

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GENOME BIOLOGY 2009年第9期10卷 R95-R95页

作者： Merz, Sandra Westermann, Benedikt Univ Bayreuth Inst Zellbiol D-95440 Bayreuth Germany Univ Bayreuth BZMB D-95440 Bayreuth Germany

Background: The mitochondrial respiratory chain produces metabolic energy by oxidative phosphorylation. Biogenesis of the respiratory chain requires the coordinated expression of two genomes: the nuclear genome encoding the vast majority of mitochondrial proteins, and the mitochondrial genome encoding a handful of mitochondrial proteins. The understanding of the molecular processes contributing to respiratory chain assembly and maintenance requires the systematic identification and functional analysis of the genes involved. Results: We pursued a systematic, genome-wide approach to define the sets of genes required for respiratory activity and maintenance and expression of the mitochondrial genome in yeast. By comparative gene deletion analysis we found an unexpected phenotypic plasticity among respiratory-deficient mutants, and we identified ten previously uncharacterized genes essential for respiratory growth (RRG1 through RRG10). Systematic functional analysis of 319 respiratory-deficient mutants revealed 16 genes essential for maintenance of the mitochondrial genome, 88 genes required for mitochondrial protein translation, and 10 genes required for expression of specific mitochondrial gene products. A group of mutants acquiring irreversible damage compromising respiratory capacity includes strains defective in assembly of the cytochrome c oxidase that were found to be particularly sensitive to aging. Conclusions: These data advance the understanding of the molecular processes contributing to maintenance of the mitochondrial genome, mitochondrial protein translation, and assembly of the respiratory chain. They revealed a number of previously uncharacterized components, and provide a comprehensive picture of the molecular processes required for respiratory activity in a simple eukaryotic cell.

关键词： Mitochondrial Genome additional data file Respiratory Growth Mitochondrial Protein Synthesis Mitochondrial Translation

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Clustering of genes into regulons using integrated modeling-COGRIM

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GENOME BIOLOGY 2007年第1期8卷 1-14页

作者： Chen, Guang Jensen, Shane T. Stoeckert, Christian J., Jr. Univ Penn Ctr Bioinformat Philadelphia PA 19104 USA Univ Penn Dept Bioengn Philadelphia PA 19104 USA Univ Penn Dept Stat Wharton Sch Philadelphia PA 19104 USA Univ Penn Dept Genet Sch Med Philadelphia PA 19104 USA

We present a Bayesian hierarchical model and Gibbs Sampling implementation that integrates gene expression, ChlP binding, and transcription factor motif data in a principled and robust fashion. COGRIM was applied to both unicellular and mammalian organisms under different scenarios of available data. In these applications, we demonstrate the ability to predict gene-transcription factor interactions with reduced numbers of false-positive findings and to make predictions beyond what is obtained when single types of data are considered.

关键词： Transcription Factor Binding Site additional data file Serum Response Factor Position Weight Matrix Network Component Analysis

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Prioritizing functional modules mediating genetic perturbations and their phenotypic effects: a global strategy

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GENOME BIOLOGY 2008年第12期9卷 R174-R174页

作者： Wang, Li Sun, Fengzhu Chen, Ting Univ So Calif Dept Biol Sci Los Angeles CA 90089 USA Tsinghua Univ MOE Key Lab Bioinformat Beijing 100084 Peoples R China Tsinghua Univ Bioinformat Div TNLIST Dept Automat Beijing 100084 Peoples R China

We have developed a global strategy based on the Bayesian network framework to prioritize the functional modules mediating genetic perturbations and their phenotypic effects among a set of overlapping candidate modules. We take lethality in Saccharomyces cerevisiae and human cancer as two examples to show the effectiveness of this approach. We discovered that lethality is more conserved at the module level than at the gene level and we identified several potentially 'new' cancer-related biological processes.

关键词： Gene Ontology additional data file Cancer Gene Functional Module Local Strategy

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Proteomic analysis of tumor necrosis factor-α resistant human breast cancer cells reveals a MEK5/Erk5-mediated epithelial-mesenchymal transition phenotype

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BREAST CANCER RESEARCH 2008年第6期10卷 1-14页

作者： Zhou, Changhua Nitschke, Ashley M. Xiong, Wei Zhang, Qiang Tang, Yan Bloch, Michael Elliott, Steven Zhu, Yun Bazzone, Lindsey Yu, David Weldon, Christopher B. Schiff, Rachel McLachlan, John A. Beckman, Barbara S. Wiese, Thomas E. Nephew, Kenneth P. Shan, Bin Burow, Matthew E. Wang, Guangdi Tulane Univ Sch Med Dept Med New Orleans LA 70112 USA Xavier Univ Dept Chem New Orleans LA 70125 USA Chengdu Blood Ctr Chengdu 610041 Sichuan Peoples R China Tulane Univ Ctr Bioenvironm Res New Orleans LA 70112 USA Xavier Univ Ctr Bioenvironm Res New Orleans LA 70112 USA Tulane Canc Ctr New Orleans LA 70112 USA Tulane Univ Sch Med Dept Pharmacol New Orleans LA 70112 USA Tulane Univ Sch Med Dept Surg New Orleans LA 70112 USA Childrens Hosp Dept Surg Boston MA 02115 USA Baylor Coll Med Dan L Duncan Canc Ctr Houston TX 77030 USA Xavier Univ Coll Pharm New Orleans LA 70125 USA Indiana Univ Sch Med Bloomington IN 47405 USA

Introduction Despite intensive study of the mechanisms of chemotherapeutic drug resistance in human breast cancer, few reports have systematically investigated the mechanisms that underlie resistance to the chemotherapy-sensitizing agent tumor necrosis factor (TNF)-alpha. additionally, the relationship between TNF-alpha resistance mediated by MEK5/Erk5 signaling and epithelial-mesenchymal transition (EMT), a process associated with promotion of invasion, metastasis, and recurrence in breast cancer, has not previously been investigated. Methods To compare differences in the proteome of the TNF-alpha resistant MCF-7 breast cancer cell line MCF-7-MEK5 (in which TNF-alpha resistance is mediated by MEK5/Erk5 signaling) and its parental TNF-a sensitive MCF-7 cell line MCF-7-VEC, two-dimensional gel electrophoresis and high performance capillary liquid chromatography coupled with tandem mass spectrometry approaches were used. Differential protein expression was verified at the transcriptional level using RT-PCR assays. An EMT phenotype was confirmed using immunofluorescence staining and gene expression analyses. A short hairpin RNA strategy targeting Erk5 was utilized to investigate the requirement for the MEK/Erk5 pathway in EMT. Results Proteomic analyses and PCR assays were used to identify and confirm differential expression of proteins. In MCF-7-MEK5 versus MCF-7-VEC cells, vimentin (VIM), glutathione-S-transferase P (GSTP1), and creatine kinase B-type (CKB) were upregulated, and keratin 8 (KRT8), keratin 19 (KRT19) and glutathione-S-transferase Mu 3 (GSTM3) were downregulated. Morphology and immunofluorescence staining for E-cadherin and vimentin revealed an EMT phenotype in the MCF-7-MEK5 cells. Furthermore, EMT regulatory genes SNAI2 (slug), ZEB1 (delta-EF1), and N-cadherin (CDH2) were upregulated, whereas E-cadherin (CDH1) was downregulated in MCF-7-MEK5 cells versus MCF-7-VEC cells. RNA interference targeting of Erk5 reversed MEK5-mediated EMT gene expression. Co

关键词： additional data file Fulvestrant Tumor Necrosis Factor Treatment Mammary Epithelial Growth Medium Gene SNAI2

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Gene function and expression level influence the insertion/fixation dynamics of distinct transposon families in mammalian introns

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GENOME BIOLOGY 2006年第12期7卷 R120-R120页

作者： Sironi, Manuela Menozzi, Giorgia Comi, Giacomo P. Cereda, Matteo Cagliani, Rachele Bresolin, Nereo Pozzoli, Uberto IRCCS E Medea Inst Sci Bioinformat Lab I-23842 Bosisio Parini LC Italy Univ Milan Osped Maggiore Policlin Mangiagalli & Regina Elena Fdn Dino Ferrari CtrDept Neurol Sci I-20100 Milan Italy

Background: Transposable elements ( TEs) represent more than 45% of the human and mouse genomes. Both parasitic and mutualistic features have been shown to apply to the host-TE relationship but a comprehensive scenario of the forces driving TE fixation within mammalian genes is still missing. Results: We show that intronic multispecies conserved sequences ( MCSs) have been affecting TE integration frequency over time. We verify that a selective economizing pressure has been acting on TEs to decrease their frequency in highly expressed genes. After correcting for GC content, MCS density and intron size, we identified TE-enriched and TE-depleted gene categories. In addition to developmental regulators and transcription factors, TE-depleted regions encompass loci that might require subtle regulation of transcript levels or precise activation timing, such as growth factors, cytokines, hormones, and genes involved in the immune response. The latter, despite having reduced frequencies of most TE types, are significantly enriched in mammalian-wide interspersed repeats ( MIRs). Analysis of orthologous genes indicated that MIR over-representation also occurs in dog and opossum immune response genes, suggesting, given the partially independent origin of MIR sequences in eutheria and metatheria, the evolutionary conservation of a specific function for MIRs located in these loci. Consistently, the core MIR sequence is over-represented in defense response genes compared to the background intronic frequency. Conclusion: Our data indicate that gene function, expression level, and sequence conservation influence TE insertion/fixation in mammalian introns. Moreover, we provide the first report showing that a specific TE family is evolutionarily associated with a gene function category.

关键词： Gene Ontology additional data file Intergenic Spacer Immune Response Gene Gene Function Category

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Comparative analysis indicates regulatory neofunctionalization of yeast duplicates

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GENOME BIOLOGY 2007年第4期8卷 R50-R50页

作者： Tirosh, Itay Barkai, Naama Weizmann Inst Sci Dept Phys Complex Syst IL-76100 Rehovot Israel Weizmann Inst Sci Dept Mol Genet IL-76100 Rehovot Israel

Background: Gene duplication provides raw material for the generation of new functions, but most duplicates are rapidly lost due to the initial redundancy in gene function. How gene function diversifies following duplication is largely unclear. Previous studies analyzed the diversification of duplicates by characterizing their coding sequence divergence. However, functional divergence can also be attributed to changes in regulatory properties, such as protein localization or expression, which require only minor changes in gene sequence. Results: We developed a novel method to compare expression profiles from different organisms and applied it to analyze the expression divergence of yeast duplicated genes. The expression profiles of Saccharomyces cerevisiae duplicate pairs were compared with those of their pre-duplication orthologs in Candida albicans. Duplicate pairs were classified into two classes, corresponding to symmetric versus asymmetric rates of expression divergence. The latter class includes 43 duplicate pairs in which only one copy has a significant expression similarity to the C. albicans ortholog. These may present cases of regulatory neofunctionalization, as supported also by their dispensability and variability. Conclusion: Duplicated genes may diversify through regulatory neofunctionalization. Notably, the asymmetry of gene sequence evolution and the asymmetry of gene expression evolution are only weakly correlated, underscoring the importance of expression analysis to elucidate the evolution of novel functions.

关键词： Gene Pair additional data file Whole Genome Duplication Expression Correlation Orthologous Pair

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Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly

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GENOME BIOLOGY 2008年第5期9卷 R80-R80页

作者： Hardman, Matthew J. Ashcroft, Gillian S. Univ Manchester Fac Life Sci Manchester M13 9PT Lancs England

Background: Multiple processes have been implicated in age-related delayed healing, including altered gene expression, intrinsic cellular changes, and changes in extracellular milieu (including hormones). To date, little attempt has been made to assess the relative contribution of each of these processes to a human aging phenomenon. The objective of this study is to determine the contribution of estrogen versus aging in age-associated delayed human wound healing. Results: Using an Affymetrix microarray-based approach we show that the differences in gene expression between male elderly and young human wounds are almost exclusively estrogen regulated. Expression of 78 probe sets was significantly decreased and 10 probe sets increased in wounds from elderly subjects (with a fold change greater than 7). A total of 83% of down-regulated probe sets and 80% of up-regulated probe sets were estrogen-regulated. Differentially regulated genes were validated at the level of gene and protein expression, with genes identified as estrogen-regulated in human confirmed as estrogen-dependent in young estrogen depleted mice in vivo. Moreover, direct estrogen regulation is demonstrated for three array-identified genes, Sele, Lypd3 and Arg1, in mouse cells in vitro. Conclusion: These findings have clear implications for our understanding of age-associated cellular changes in the context of wound healing, the latter acting as a paradigm for other age-related repair and maintenance processes, and suggest estrogen has a more profound influence on aging than previously thought.

关键词： Elderly Subject additional data file Arginase Secretory Leukocyte Protease Inhibitor Expression Analysis Systematic Explorer

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Metabolic-network-driven analysis of bacterial ecological strategies

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GENOME BIOLOGY 2009年第6期10卷 R61-R61页

作者： Freilich, Shiri Kreimer, Anat Borenstein, Elhanan Yosef, Nir Sharan, Roded Gophna, Uri Ruppin, Eytan Tel Aviv Univ Blavatnik Sch Comp Sci IL-69978 Tel Aviv Israel Tel Aviv Univ Sch Med IL-69978 Tel Aviv Israel Tel Aviv Univ Sch Math Sci IL-69978 Tel Aviv Israel Stanford Univ Dept Biol Sci Stanford CA 94305 USA Santa Fe Inst Santa Fe NM 87501 USA Tel Aviv Univ Fac Life Sci Dept Mol Microbiol & Biotechnol IL-69978 Tel Aviv Israel

Background: The growth-rate of an organism is an important phenotypic trait, directly affecting its ability to survive in a given environment. Here we present the first large scale computational study of the association between ecological strategies and growth rate across 113 bacterial species, occupying a variety of metabolic habitats. Genomic data are used to reconstruct the species' metabolic networks and habitable metabolic environments. These reconstructions are then used to investigate the typical ecological strategies taken by organisms in terms of two basic species-specific measures: metabolic variability - the ability of a species to survive in a variety of different environments;and co-habitation score vector - the distribution of other species that co-inhabit each environment. Results: We find that growth rate is significantly correlated with metabolic variability and the level of co-habitation (that is, competition) encountered by an organism. Most bacterial organisms adopt one of two main ecological strategies: a specialized niche with little co-habitation, associated with a typically slow rate of growth;or ecological diversity with intense co-habitation, associated with a typically fast rate of growth. Conclusions: The pattern observed suggests a universal principle where metabolic flexibility is associated with a need to grow fast, possibly in the face of competition. This new ability to produce a quantitative description of the growth rate-metabolism-community relationship lays a computational foundation for the study of a variety of aspects of the communal metabolic life.

关键词： Metabolic Network additional data file Random Environment Fast Growth Rate Ecological Strategy

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DetectiV: visualization, normalization and significance testing for pathogen-detection microarray data

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GENOME BIOLOGY 2007年第9期8卷 R190-R190页

作者： Watson, Michael Dukes, Juliet Abu-Median, Abu-Bakr King, Donald P. Britton, Paul Inst Anim Hlth Newbury RG20 7NN Berks England Inst Anim Hlth Pirbright GU24 0NF Surrey England

DNA microarrays offer the possibility of testing for the presence of thousands of micro-organisms in a single experiment. However, there is a lack of reliable bioinformatics tools for the analysis of such data. We have developed DetectiV, a package for the statistical software R. DetectiV offers powerful yet simple visualization, normalization and significance testing tools. We show that DetectiV performs better than previously published software on a large, publicly available dataset.

关键词： Respiratory Syncytial Virus additional data file Correct Result Infectious Bronchitis Virus Human Herpesvirus

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Coverage and error models of protein-protein interaction data by directed graph analysis

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GENOME BIOLOGY 2007年第9期8卷 R186-R186页

作者： Chiang, Tony Scholtens, Denise Sarkar, Deepayan Gentleman, Robert Huber, Wolfgang European Bioinformat Inst EMBL Cambridge CB10 1SD England Fred Hutchinson Canc Res Ctr Computat Biol Grp Seattle WA 98109 USA Northwestern Univ Dept Prevent Med Chicago IL 60611 USA

Using a directed graph model for bait to prey systems and a multinomial error model, we assessed the error statistics in all published large-scale datasets for Saccharomyces cerevisiae and characterized them by three traits: the set of tested interactions, artifacts that lead to false-positive or false-negative observations, and estimates of the stochastic error rates that affect the data. These traits provide a prerequisite for the estimation of the protein interactome and its modules.

关键词： additional data file Protein Pair Stochastic Error Protein Interaction data Bait Protein

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