title: Revealing molecular mechanisms by integrating high-dimensional functional screens with protein interaction data.
abstract: Functional genomics screens using multi-parametric assays are powerful approaches for identifying genes involved in particular cellular processes. However, they suffer from problems like noise, and often provide little insight into molecular mechanisms. A bottleneck for addressing these issues is the lack of computational methods for the systematic integration of multi-parametric phenotypic datasets with molecular interactions. Here, we present Integrative Multi Profile Analysis of Cellular Traits (IMPACT). The main goal of IMPACT is to identify the most consistent phenotypic profile among interacting genes. This approach utilizes two types of external information: sets of related genes (IMPACT-sets) and network information (IMPACT-modules). Based on the notion that interacting genes are more likely to be involved in similar functions than non-interacting genes, this data is used as a prior to inform the filtering of phenotypic profiles that are similar among interacting genes. IMPACT-sets selects the most frequent profile among a set of related genes. IMPACT-modules identifies sub-networks containing genes with similar phenotype profiles. The statistical significance of these selections is subsequently quantified via permutations of the data. IMPACT (1) handles multiple profiles per gene, (2) rescues genes with weak phenotypes and (3) accounts for multiple biases e.g. caused by the network topology. Application to a genome-wide RNAi screen on endocytosis showed that IMPACT improved the recovery of known endocytosis-related genes, decreased off-target effects, and detected consistent phenotypes. Those findings were confirmed by rescreening 468 genes. Additionally we validated an unexpected influence of the IGF-receptor on EGF-endocytosis. IMPACT facilitates the selection of high-quality phenotypic profiles using different types of independent information, thereby supporting the molecular interpretation of functional screens.
authors.affiliation: Biotechnology Center, TU Dresden, Dresden, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Simeone
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsico
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Claudio
authors.initials: C
authors.lastname: Collinet
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Thierry
authors.initials: T
authors.lastname: Galvez
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany; Belozersky Institute of Physico-Chemical Biology & Faculty of Bioengineering and Bioinformatics, Moscow State University, Moscow, Russia.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Kalaidzidis
authors.affiliation: Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Marino
authors.initials: M
authors.lastname: Zerial
authors.affiliation: Biotechnology Center, TU Dresden, Dresden, Germany; Center for Regenerative Therapy, Dresden, Germany; University of Cologne, Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beyer
mesh_terms: D019295:Computational Biology / Q000379:methods*; D004705:Endocytosis; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D009369:Neoplasms; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D011506:Proteins