Preferential Binding of HIF-1 to Transcriptionally Active Loci Determines Cell-type Specific Response to Hypoxia

Abstract

Background: Hypoxia-inducible factor 1 (HIF-1) plays a key role in cellular adaptation to hypoxia. To better understand the determinants of HIF-1 binding and transactivation, we used ChIP-chip and gene expression profiling to define the relationship between the epigenetic landscape, sites of HIF-1 binding, and genes transactivated by hypoxia in two cell lines. Results: We found that when cells were acutely subjected to hypoxia, HIF-1 preferentially bound to loci that were already transcriptionally active under normal growth conditions characterized by the presence of histone H3 lysine 4 methylation, the presence of RNA polymerase II, and basal production of mRNA. Cell type-specific differences in HIF-1 binding were largely attributable to differences in the basal gene expression patterns in the cells prior to the onset of hypoxia. Conclusions: These results suggest that the repertoire of genes active in a cell (for example, through lineage specific transcription factors) defines the subset of genes that are permissive for binding and transactivation by stimulus-responsive transcription factors.