tailieunhanh - Báo cáo khoa học: Seed-based systematic discovery of specific transcription factor target genes

Reliable prediction of specific transcription factor target genes is a major challenge in systems biology and functional genomics. Current sequence-based methods yield many false predictions, due to the short and degenerated DNA-binding motifs. | ễFEBS Journal Seed-based systematic discovery of specific transcription factor target genes Ralf Mrowka1 2 3 Nils Bluthgen4 and Michael Fahling1 3 1 Paul-Ehrlich-Zentrum fur Experimentelle Medizin Berlin Germany 2 AG Systems Biology - ComputationalPhysiology Berlin Germany 3 Johannes-Muller-Institut fur Physiologie Charite-Universitatsmedizin Berlin Germany 4 Schoolof ChemicalEngineering and AnalyticalSciences Manchester Interdisciplinary Biocentre University of Manchester UK Keywords feedback glaucoma NF-kB optineurin transcription factor target prediction Correspondence R. Mrowka Paul-Ehrlich-Zentrum fur Experimentelle Medizin AG Systems Biology - ComputationalPhysiology Tucholskystr. 2 D-10117 Berlin Germany Fax 49 30 450528972 Tel 49 30 450528218 E-mail Received 26 February 2008 revised 1 April 2008 accepted 16 April 2008 doi Reliable prediction of specific transcription factor target genes is a major challenge in systems biology and functional genomics. Current sequence-based methods yield many false predictions due to the short and degenerated DNA-binding motifs. Here we describe a new systematic genome-wide approach the seed-distribution-distance method that searches large-scale genome-wide expression data for genes that are similarly expressed as known targets. This method is used to identify genes that are likely targets allowing sequence-based methods to focus on a subset of genes giving rise to fewer false-positive predictions. We show by cross-validation that this method is robust in recovering specific target genes. Furthermore this method identifies genes with typical functions and binding motifs of the seed. The method is illustrated by predicting novel targets of the transcription factor nuclear factor kappaB NF-kB . Among the new targets is optineurin which plays a key role in the pathogenesis of acquired blindness caused by adult-onset primary open-angle glaucoma. We show experimentally that