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Genome-wide Association of Hypoxia-inducible Factor (HIF)-1α and HIF-2α DNA Binding with Expression Profiling of Hypoxia-inducible Transcripts

The Journal of biological chemistry, 2009-06, Vol.284 (25), p.16767-16775 [Peer Reviewed Journal]

2009 © 2009 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology. ;2009 by The American Society for Biochemistry and Molecular Biology, Inc. ;ISSN: 0021-9258 ;EISSN: 1083-351X ;DOI: 10.1074/jbc.M901790200 ;PMID: 19386601

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  • Title:
    Genome-wide Association of Hypoxia-inducible Factor (HIF)-1α and HIF-2α DNA Binding with Expression Profiling of Hypoxia-inducible Transcripts
  • Author: Mole, David R. ; Blancher, Christine ; Copley, Richard R. ; Pollard, Patrick J. ; Gleadle, Jonathan M. ; Ragoussis, Jiannis ; Ratcliffe, Peter J.
  • Subjects: Transcription, Chromatin, and Epigenetics
  • Is Part Of: The Journal of biological chemistry, 2009-06, Vol.284 (25), p.16767-16775
  • Description: Hypoxia-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-α 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-1α or HIF-2α at high stringency. Analysis of these sequences confirmed an identical core binding motif for HIF-1α and HIF-2α (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-1α- versus HIF-2α-binding sites revealed that whereas some loci bound HIF-1α in isolation, many bound both isoforms with similar affinity. Despite high-affinity binding to multiple promoters, HIF-2α contributed to few, if any, of the transcriptional responses to acute hypoxia at these loci. Given emerging evidence for biologically distinct functions of HIF-1α versus HIF-2α understanding the mechanisms restricting HIF-2α activity will be of interest.
  • Publisher: 9650 Rockville Pike, Bethesda, MD 20814, U.S.A: Elsevier Inc
  • Language: English
  • Identifier: ISSN: 0021-9258
    EISSN: 1083-351X
    DOI: 10.1074/jbc.M901790200
    PMID: 19386601
  • Source: Open Access: PubMed Central
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