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J. Biol. Chem., Vol. 281, Issue 22, 15215-15226, June 2, 2006
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Concordant Regulation of Gene Expression by Hypoxia and 2-Oxoglutarate-dependent Dioxygenase Inhibition
THE ROLE OF HIF-1
, HIF-2, AND OTHER PATHWAYS*
12
From the
Oxygen Sensing Group, The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, and the Genomics Group, Wellcome Trust Centre for Human Genetics, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Oxford OX3 7BN, United Kingdom
Studies of gene regulation by oxygen have revealed novel signal pathways that regulate the hypoxia-inducible factor (HIF) transcriptional system through post-translational hydroxylation of specific prolyl and asparaginyl residues in HIF- subunits. These oxygen-sensitive modifications are catalyzed by members of the 2-oxoglutarate (2-OG) dioxygenase family (PHD1, PHD2, PHD3, and FIH-1), raising an important question regarding the extent of involvement of these and other enzymes of the same family in directing the global changes in gene expression that are induced by hypoxia. To address this, we compared patterns of gene expression induced by hypoxia and by a nonspecific 2-OG-dependent dioxygenase inhibitor, dimethyloxalylglycine (DMOG), among a set of 22,000 transcripts, by microarray analysis of MCF7 cells. By using short interfering RNA-based suppression of HIF- subunits, we also compared responses that were dependent on, or independent of, the HIF system. Results revealed striking concordance between patterns of gene expression induced by hypoxia and by DMOG, indicating the central involvement of 2-OG-dependent dioxygenases in oxygen-regulated gene expression. Many of these responses were suppressed by short interfering RNAs directed against HIF-1 and HIF-2, with HIF-1 suppression manifesting substantially greater effects than HIF-2 suppression, supporting the importance of HIF pathways. Nevertheless, the definition of genes regulated by both hypoxia and DMOG, but not HIF, distinguished other pathways most likely involving the action of 2-OG-dependent dioxygenases on non-HIF substrates.
Received for publication, October 20, 2005 , and in revised form, February 28, 2006.
* This work was supported by the Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables 1–6.
The microarray data can be accessed through Gene Expression Repository under GEO accession number GSE3188 [NCBI GEO] .
1 To whom correspondence may be addressed. Tel.: 44-1865-287526; Fax: 44-1865-287501; E-mail: ioannisr{at}well.ox.ac.uk. 2 To whom correspondence may be addressed. Tel.: 44-1865-287788; Fax: 44-1865-287787; E-mail: jgleadle{at}well.ox.ac.uk.
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