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High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq
Open accessAbstract
Hypoxia-inducible factor (HIF) regulates the major transcriptional cascade central to the response of all mammalian cells to alterations in oxygen tension. Expression arrays indicate that many hundreds of genes are regulated by this pathway, controlling diverse processes that in turn orchestrate both oxygen delivery and utilization. However, the extent to which HIF exerts direct versus indirect control over gene expression together with the factors dictating the range of HIF-regulated genes remains unclear. Using chromatin immunoprecipitation linked to high throughput sequencing, we identify HIF-binding sites across the genome, independently of gene architecture. Using gene set enrichment analysis, we demonstrate robust associations with the regulation of gene expression by HIF, indicating that these sites operate over long genomic intervals. Analysis of HIF-binding motifs demonstrates sequence preferences outside of the core RCGTG-binding motif but does not reveal any additional absolute sequence requirements. Across the entire genome, only a small proportion of these potential binding sites are bound by HIF, although occupancy of potential sites was enhanced approximately 20-fold at normoxic DNAse1 hypersensitivity sites (irrespective of distance from promoters), suggesting that epigenetic regulation of chromatin may have an important role in defining the response to hypoxia.
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“A study using chromatin immunoprecipitation followed by next-generation high-throughput sequencing (ChIP-seq) showed that HIF binding sites exist outside of promoter sequences and that HIF binds to other sites as well as the core A/GCGTG motif (Schodel et al., 2011).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Schodel et al., 2011
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“Notwithstanding these distinctions, the global architecture of HIF-1- and HIF-2-dependent target gene networks remains largely conserved across different cell types [7,66,68,70]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [68]
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“This was particularly true for HIF-2α, for which as many as 70% of the identified HIF-2 binding sites lay outside promoter regions.”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Schodel et al., 2011
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“Promoter-proximal HIF-1 binding correlates with a higher transcript abundance [68,71,79,82]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [68]
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“Most functional HREs reside within open chromatin [68,80,81] and HIF-1 preferentially binds promoter-proximal regions, whereas HIF-2 more frequently occupies distal enhancers”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [68]
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“Within the nucleus, transcriptionally active HIF heterodimers bind hypoxia-responsive elements (HREs) containing an asymmetric E-box core motif (RCGTG, where R = A or G) [68,76]”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [68]
In the citing paper
“In the nucleus, HIF-α subunits dimerize with aryl hydrocarbon receptor nuclear translocator (ARNT) and bind to hypoxia-responsive elements in target genes to activate gene transcription by recruiting transcriptional coactivators including p300/CBP”
From Hypoxic control of metastasis (2016) · cites this paper as [15]
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,836
Sequence logos: a new way to display consensus sequences
Schneider, T. D., & Stephens, R. M. (1990) · Nucleic Acids Research · doi:10.1093/nar/18.20.6097 · Cited by 3,354
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
Kaelin, W. G., & Ratcliffe, P. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.04.009 · Cited by 3,251
Self-citationSemenza, G. L., & Wang, G. L. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.12.5447 · Cited by 2,617
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068
Self-citationAn oestrogen-receptor-α-bound human chromatin interactome
Fullwood, M. J., Liu, M. H., Pan, Y. F., Liu, J., Han, X., Mohamed, Y. B., Orlov, Y. L., Velkov, S., Ho, A., Poh, H. M., et al. (2009) · Nature · doi:10.1038/nature08497 · Cited by 1,752
Hypoxia signalling in cancer and approaches to enforce tumour regression
Pouysségur, J., Dayan, F., & Mazure, N. M. (2006) · Nature · doi:10.1038/nature04871 · Cited by 1,676
Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude
Yi, X., Liang, Y., Huerta-Sanchez, E., Jin, X., Cuo, Z. X. P., Pool, J. E., Xu, X., Jiang, H., Vinckenbosch, N., Korneliussen, T. S., et al. (2010) · Science · doi:10.1126/science.1190371 · Cited by 1,611
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Sorted by citations
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,836
Hypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy
Semenza, G. L. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.01.005 · Cited by 1,514
Rankin, E. B., & Giaccia, A. J. (2016) · Science · doi:10.1126/science.aaf4405 · Cited by 1,340
Metadata
- Authors
- Schödel, J., Oikonomopoulos, S., Ragoussis, J., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R.
- Affiliations
- University of Oxford (GB)
- Centre for Human Genetics (GB)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2011-06-09
- Volume
- 117
- Issue
- 23
- Pages
- e207-e217
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3374576
- OpenAlex
- W1969734439
- Cited by
- 724
- References
- 50
- Citations by year
- 2026: 25 · 2025: 34 · 2024: 32 · 2023: 43 · 2022: 63 · 2021: 72 · 2020: 62 · 2019: 55 · 2018: 45 · 2017: 52 · 2016: 56 · 2015: 44 · 2014: 50 · 2013: 61 · 2012: 22
- FWCI
- 15.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (090532)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- hypoxia-inducible factor, transcriptional regulation, hypoxia response, oxygen partial pressure, chromatin accessibility, epigenetic regulation, gene set enrichment analysis, sequence motifs
- MeSH terms
- Chromosome Mapping, Female, Humans, Oxygen, Genome, Human, Response Elements, Epigenesis, Genetic, Cell Line, Tumor, Chromatin Immunoprecipitation, Basic Helix-Loop-Helix Proteins, Genome-Wide Association Study
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