title: Orthogonal matrix factorization enables integrative analysis of multiple RNA binding proteins.
abstract: RNA binding proteins (RBPs) play important roles in post-transcriptional control of gene expression, including splicing, transport, polyadenylation and RNA stability. To model protein-RNA interactions by considering all available sources of information, it is necessary to integrate the rapidly growing RBP experimental data with the latest genome annotation, gene function, RNA sequence and structure. Such integration is possible by matrix factorization, where current approaches have an undesired tendency to identify only a small number of the strongest patterns with overlapping features. Because protein-RNA interactions are orchestrated by multiple factors, methods that identify discriminative patterns of varying strengths are needed.
  
  
  
  We have developed an integrative orthogonality-regularized nonnegative matrix factorization (iONMF) to integrate multiple data sources and discover non-overlapping, class-specific RNA binding patterns of varying strengths. The orthogonality constraint halves the effective size of the factor model and outperforms other NMF models in predicting RBP interaction sites on RNA. We have integrated the largest data compendium to date, which includes 31 CLIP experiments on 19 RBPs involved in splicing (such as hnRNPs, U2AF2, ELAVL1, TDP-43 and FUS) and processing of 3'UTR (Ago, IGF2BP). We show that the integration of multiple data sources improves the predictive accuracy of retrieval of RNA binding sites. In our study the key predictive factors of protein-RNA interactions were the position of RNA structure and sequence motifs, RBP co-binding and gene region type. We report on a number of protein-specific patterns, many of which are consistent with experimentally determined properties of RBPs.
  
  
  
  The iONMF implementation and example datasets are available at https://github.com/mstrazar/ionmf
  
  
  
  : tomaz.curk@fri.uni-lj.si
  
  
  
  Supplementary data are available at Bioinformatics online.
authors.affiliation: University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, SI 1000, Slovenia.
authors.forename: Martin
authors.initials: M
authors.lastname: Stražar
authors.affiliation: University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, SI 1000, Slovenia.
authors.forename: Marinka
authors.initials: M
authors.lastname: Žitnik
authors.affiliation: University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, SI 1000, Slovenia Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Blaž
authors.initials: B
authors.lastname: Zupan
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Jernej
authors.initials: J
authors.lastname: Ule
authors.affiliation: University of Ljubljana, Faculty of Computer and Information Science, Ljubljana, SI 1000, Slovenia.
authors.forename: Tomaž
authors.initials: T
authors.lastname: Curk
mesh_terms: D001665:Binding Sites; D003625:Data Collection; D066264:Datasets as Topic; D008958:Models, Molecular; D012313:RNA; D016601:RNA-Binding Proteins
chemical_list: D016601:RNA-Binding Proteins; D012313:RNA