title: ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes.
abstract: ChIP-on-chip has emerged as a powerful tool to dissect the complex network of regulatory interactions between transcription factors and their targets. However, most ChIP-on-chip analysis methods use conservative approaches aimed at minimizing false-positive transcription factor targets. We present a model with improved sensitivity in detecting binding events from ChIP-on-chip data. Its application to human T cells, followed by extensive biochemical validation, reveals that 3 oncogenic transcription factors, NOTCH1, MYC, and HES1, bind to several thousand target gene promoters, up to an order of magnitude increase over conventional analysis methods. Gene expression profiling upon NOTCH1 inhibition shows broad-scale functional regulation across the entire range of predicted target genes, establishing a closer link between occupancy and regulation. Finally, the increased sensitivity reveals a combinatorial regulatory program in which MYC cobinds to virtually all NOTCH1-bound promoters. Overall, these results suggest an unappreciated complexity of transcriptional regulatory networks and highlight the fundamental importance of genome-scale analysis to represent transcriptional programs.
authors.affiliation: Department of Biomedical Informatics, Joint Centers for Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Margolin
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.forename: Pavel
authors.initials: P
authors.lastname: Sumazin
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.forename: Gustavo
authors.initials: G
authors.lastname: Stolovitzky
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods* / Q000592:standards; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D013601:T-Lymphocytes; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C497761:NOTCH1 protein, human; C078493:HES1 protein, human