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Hypoxia is a hallmark of tumors, and adaptation is mostly mediated by the transcription factors Hypoxia Inducible Factor-1 (HIF-1) and HIF-2. Hypoxia results in accumulation of HIFs, which bind to the cognate Hypoxia-Response Element (HRE) and transactivate target genes that contribute to many aspects of cancer progression. To better understand the mechanisms of HIF-mediated transactivation, we have mapped HIF-1 binding sites on a genome-wide scale using chromatin immunoprecipitation followed by analysis on tiled genomic arrays (ChIP-on-chip). Triplicate HIF-1 ChIP’ed DNA from both normoxic and hypoxic HepG2 cells are hybridized onto Affymetrix Human Tiling Arrays 2.0R, which contain probes across the whole genome with a 35 base resolution. Using model-based analysis tiling array algorithm, MAT, we have identified both known and novel HIF-1 binding sites and target genes. In contrast to estrogen receptor (ER), most HIF-1 binding sites are found in promoter regions. Integration of ChIP-on-chip with gene expression profiling and motif scanning data has revealed new details of HIF-1 mediated gene transactivation, as well as mechanisms of suppression of gene activation.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA