Article: Genome-wide identification of hypoxia-inducible factor binding sites and target genes by a probabilistic model integrating transcription-profiling data and in silico binding site prediction
Nucleic acids research. 2010 Apr., v. 38, no. 7
2010
Abstract: The transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Hence, the complete identification of HIF targets is essential for understanding the cellular responses to hypoxia. Herein we ... ...
| Abstract | The transcriptional response driven by Hypoxia-inducible factor (HIF) is central to the adaptation to oxygen restriction. Hence, the complete identification of HIF targets is essential for understanding the cellular responses to hypoxia. Herein we describe a computational strategy based on the combination of phylogenetic footprinting and transcription profiling meta-analysis for the identification of HIF-target genes. Comparison of the resulting candidates with published HIF1a genome-wide chromatin immunoprecipitation indicates a high sensitivity (78%) and specificity (97.8%). To validate our strategy, we performed HIF1a chromatin immunoprecipitation on a set of putative targets. Our results confirm the robustness of the computational strategy in predicting HIF-binding sites and reveal several novel HIF targets, including RE1-silencing transcription factor co-repressor (RCOR2). In addition, mapping of described polymorphisms to the predicted HIF-binding sites identified several single-nucleotide polymorphisms (SNPs) that could alter HIF binding. As a proof of principle, we demonstrate that SNP rs17004038, mapping to a functional hypoxia response element in the macrophage migration inhibitory factor (MIF) locus, prevents induction of this gene by hypoxia. Altogether, our results show that the proposed strategy is a powerful tool for the identification of HIF direct targets that expands our knowledge of the cellular adaptation to hypoxia and provides cues on the inter-individual variation in this response. |
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| Keywords | binding sites ; chromatin ; genes ; hypoxia ; loci ; macrophage migration inhibitory factors ; meta-analysis ; nucleic acids ; oxygen ; phylogeny ; precipitin tests ; prediction ; probabilistic models ; single nucleotide polymorphism ; transcription (genetics) ; transcription factors |
| Language | English |
| Dates of publication | 2010-04 |
| Size | p. 2332-2345. |
| Document type | Article |
| ZDB-ID | 186809-3 |
| ISSN | 0301-5610 ; 0305-1048 |
| ISSN | 0301-5610 ; 0305-1048 |
| DOI | 10.1093/nar/gkp1205 |
| Database | NAL-Catalogue (AGRICOLA) |
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