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Molecular cell v.65 no.4, 2017년, pp.761 - 774.e5   SCI SCIE
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Active Interaction Mapping Reveals the Hierarchical Organization of Autophagy

Kramer, Michael H. (Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA ) ; Farré, Jean-Claude (Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ; Mitra, Koyel (Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA ) ; Yu, Michael Ku (Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA ) ; Ono, Keiichiro (Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA ) ; Demchak, Barry (Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA ) ; Licon, Katherine (Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA ) ; Flagg, Mitchell (Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA ) ; Balakrishnan, Rama (Department of Genetics, Stanford University, Stanford, CA 94304, USA ) ; Cherry, J. Michael (Department of Genetics, Stanford University, Stanford, CA 94304, USA ) ; Subramani, Suresh (Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA ) ; Ideker, Trey ;
  • 초록  

    Summary We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces , captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at http://atgo.ucsd.edu/. Highlights Diverse -omics data integrated to assemble a unified hierarchical model of autophagy Post hoc analysis prioritizes the most informative future data types Consequently, 156,364 genetic interactions measured in autophagy-activating conditions Multiple new functions involve Gyp1, Atg24, Atg26, Ssd1, Did4, Stp22, and others Graphical Abstract [DISPLAY OMISSION]


  • 주제어

    autophagy .   systems biology .   hierarchical modeling .   active interaction mapping .   yeast .   human.  

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