ChIP-on-chip significance analysis reveals large-scale binding and regulation by human transcription factor oncogenes

Adam A. Margolin, Teresa Palomero, Pavel Sumazin, Andrea Califano, Adolfo A. Ferrando, Gustavo Stolovitzky

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58 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)244-249
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number1
DOIs
StatePublished - Jan 6 2009

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Keywords

  • Regulatory networks
  • Systems biology
  • T cell lymphoblastic leukemia
  • Transcriptional regulation

ASJC Scopus subject areas

  • General

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