title: Predictive regulatory models in Drosophila melanogaster by integrative inference of transcriptional networks.
abstract: Gaining insights on gene regulation from large-scale functional data sets is a grand challenge in systems biology. In this article, we develop and apply methods for transcriptional regulatory network inference from diverse functional genomics data sets and demonstrate their value for gene function and gene expression prediction. We formulate the network inference problem in a machine-learning framework and use both supervised and unsupervised methods to predict regulatory edges by integrating transcription factor (TF) binding, evolutionarily conserved sequence motifs, gene expression, and chromatin modification data sets as input features. Applying these methods to Drosophila melanogaster, we predict ∼300,000 regulatory edges in a network of ∼600 TFs and 12,000 target genes. We validate our predictions using known regulatory interactions, gene functional annotations, tissue-specific expression, protein-protein interactions, and three-dimensional maps of chromosome conformation. We use the inferred network to identify putative functions for hundreds of previously uncharacterized genes, including many in nervous system development, which are independently confirmed based on their tissue-specific expression patterns. Last, we use the regulatory network to predict target gene expression levels as a function of TF expression, and find significantly higher predictive power for integrative networks than for motif or ChIP-based networks. Our work reveals the complementarity between physical evidence of regulatory interactions (TF binding, motif conservation) and functional evidence (coordinated expression or chromatin patterns) and demonstrates the power of data integration for network inference and studies of gene regulation at the systems level.
authors.affiliation: Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Marbach
authors.forename: Sushmita
authors.initials: S
authors.lastname: Roy
authors.forename: Ferhat
authors.initials: F
authors.lastname: Ay
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Meyer
authors.forename: Rogerio
authors.initials: R
authors.lastname: Candeias
authors.forename: Tamer
authors.initials: T
authors.lastname: Kahveci
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bristow
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
mesh_terms: D000818:Animals; D001483:Base Sequence; D042002:Chromatin Assembly and Disassembly; D047369:Chromatin Immunoprecipitation; D002874:Chromosome Mapping / Q000379:methods; D002875:Chromosomes / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D017124:Conserved Sequence; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D049750:Genome, Insect; D016014:Linear Models; D008957:Models, Genetic; D058977:Molecular Sequence Annotation; D009420:Nervous System / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D059372:Nucleotide Motifs; D009928:Organ Specificity; D011485:Protein Binding; D025941:Protein Interaction Mapping; D050436:Regulatory Elements, Transcriptional; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors