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Nucleic Acids Research Advance Access originally published online on June 2, 2009
Nucleic Acids Research 2009 37(14):4587-4602; doi:10.1093/nar/gkp425
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Nucleic Acids Research, 2009, Vol. 37, No. 14 4587-4602
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gene Regulation, Chromatin and Epigenetics

An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia

Yair Benita1, Hirotoshi Kikuchi2, Andrew D. Smith3, Michael Q. Zhang3, Daniel C. Chung2 and Ramnik J. Xavier1,2,*

1Center for Computational and Integrative Biology, 2Gastrointestinal Unit, Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 and 3Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA

*To whom correspondence should be addressed. Tel: 617 643 3331; Fax: 617 643 3328; Email: xavier{at}molbio.mgh.harvard.edu

Received April 20, 2009. Revised May 6, 2009. Accepted May 8, 2009.

The transcription factor Hypoxia-inducible factor 1 (HIF-1) plays a central role in the transcriptional response to oxygen flux. To gain insight into the molecular pathways regulated by HIF-1, it is essential to identify the downstream-target genes. We report here a strategy to identify HIF-1-target genes based on an integrative genomic approach combining computational strategies and experimental validation. To identify HIF-1-target genes microarrays data sets were used to rank genes based on their differential response to hypoxia. The proximal promoters of these genes were then analyzed for the presence of conserved HIF-1-binding sites. Genes were scored and ranked based on their response to hypoxia and their HIF-binding site score. Using this strategy we recovered 41% of the previously confirmed HIF-1-target genes that responded to hypoxia in the microarrays and provide a catalogue of predicted HIF-1 targets. We present experimental validation for ANKRD37 as a novel HIF-1-target gene. Together these analyses demonstrate the potential to recover novel HIF-1-target genes and the discovery of mammalian-regulatory elements operative in the context of microarray data sets.


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