title: Computation-based discovery of related transcriptional regulatory modules and motifs using an experimentally validated combinatorial model.
abstract: Gene expression is regulated by transcription factors that interact with cis-regulatory elements. Predicting these elements from sequence data has proven difficult. We describe here a successful computational search for elements that direct expression in a particular temporal-spatial pattern in the Drosophila embryo, based on a single well characterized enhancer model. The fly genome was searched to identify sequence elements containing the same combination of transcription factors as those found in the model. Experimental evaluation of the search results demonstrates that our method can correctly predict regulatory elements and highlights the importance of functional testing as a means of identifying false-positive results. We also show that the search results enable the identification of additional relevant sequence motifs whose functions can be empirically validated. This approach, combined with gene expression and phylogenetic sequence data, allows for genome-wide identification of related regulatory elements, an important step toward understanding the genetic regulatory networks involved in development.
authors.affiliation: Howard Hughes Medical Institute and Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Marc S
authors.initials: MS
authors.lastname: Halfon
authors.forename: Yonatan
authors.initials: Y
authors.lastname: Grad
authors.forename: George M
authors.initials: GM
authors.lastname: Church
authors.forename: Alan M
authors.initials: AM
authors.lastname: Michelson
mesh_terms: D024509:3' Flanking Region / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins; D001482:Base Composition / Q000235:genetics; D001483:Base Sequence; D002874:Chromosome Mapping; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D017124:Conserved Sequence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D017344:Genes, Insect / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D064326:MEF2 Transcription Factors; D008648:Mesoderm / Q000737:chemistry / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D018006:Myogenic Regulatory Factors; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D064326:MEF2 Transcription Factors; C499409:Mef2 protein, Drosophila; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C052837:eve protein, Drosophila