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dc.contributor.authorMole, D
dc.contributor.authorBlancher, C
dc.contributor.authorCopley, R
dc.contributor.authorGleadle, Jonathan
dc.contributor.authorLiu, C
dc.contributor.authorRagoussis, J
dc.contributor.authorRatcliffe, P
dc.identifier.citationMole DR, Blancher C, Copley RR, Pollard PJ, Gleadle JM, Ragoussis J, Ratcliffe PJ. Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts. Journal of Biological Chemistry. 2009 Jun 19;284(25):16767-75.en
dc.descriptionThis article is open access and is available at the linked URLen
dc.description.abstractHypoxia-inducible factor (HIF) controls an extensive range of adaptive responses to hypoxia. To better understand this transcriptional cascade we performed genome-wide chromatin immunoprecipitation using antibodies to two major HIF-alpha subunits, and correlated the results with genome-wide transcript profiling. Within a tiled promoter array we identified 546 and 143 sequences that bound, respectively, to HIF-1alpha or HIF-2alpha at high stringency. Analysis of these sequences confirmed an identical core binding motif for HIF-1alpha and HIF-2alpha (RCGTG) but demonstrated that binding to this motif was highly selective, with binding enriched at distinct regions both upstream and downstream of the transcriptional start. Comparison of HIF-promoter binding data with bidirectional HIF-dependent changes in transcript expression indicated that whereas a substantial proportion of positive responses (>20% across all significantly regulated genes) are direct, HIF-dependent gene suppression is almost entirely indirect. Comparison of HIF-1alpha- versus HIF-2alpha-binding sites revealed that whereas some loci bound HIF-1alpha in isolation, many bound both isoforms with similar affinity. Despite high-affinity binding to multiple promoters, HIF-2alpha contributed to few, if any, of the transcriptional responses to acute hypoxia at these loci. Given emerging evidence for biologically distinct functions of HIF-1alpha versus HIF-2alpha understanding the mechanisms restricting HIF-2alpha activity will be of interest.en
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen
dc.rightsCopyright © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.en
dc.titleGenome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripten
dc.rights.holderAmerican Society for Biochemistry and Molecular Biologyen
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