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

Content Provider	PubMed Central
Author	Mole, David R. Blancher, Christine Copley, Richard R. Pollard, Patrick J. Gleadle, Jonathan M. Ragoussis, Jiannis Ratcliffe, Peter J.
Abstract	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.
Related Links	http://dx.doi.org/10.1074/jbc.m901790200
Ending Page	16775
Page Count	9
Starting Page	16767
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	25
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-06-19
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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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

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