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Cited by 195Cancer, Hypoxia, and MetabolismGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

Inherent DNA‐binding specificities of the HIF‐1α and HIF‐2α transcription factors in chromatin

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Smythies, James A, Sun, Min, Masson, Norma, Salama, Rafik, Simpson, Peter D, Murray, Elizabeth, Neumann, Viviana, Cockman, Matthew E +3 more·2019·The EMBO Reports
DOI 10.15252/embr.201846401PMC PMC6322389
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Abstract

Hypoxia‐inducible factor (HIF) is the major transcriptional regulator of cellular responses to hypoxia. The two principal HIF‐α isoforms, HIF‐1α and HIF‐2α, are progressively stabilized in response to hypoxia and form heterodimers with HIF‐1β to activate a broad range of transcriptional responses. Here, we report on the pan‐genomic distribution of isoform‐specific HIF binding in response to hypoxia of varying severity and duration, and in response to genetic ablation of each HIF‐α isoform. Our findings reveal that, despite an identical consensus recognition sequence in DNA, each HIF heterodimer loads progressively at a distinct repertoire of cell‐type‐specific sites across the genome, with little evidence of redistribution under any of the conditions examined. Marked biases towards promoter‐proximal binding of HIF‐1 and promoter‐distant binding of HIF‐2 were observed under all conditions and were consistent in multiple cell type. The findings imply that each HIF isoform has an inherent property that determines its binding distribution across the genome, which might be exploited to therapeutically target the specific transcriptional output of each isoform independently.

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  • Promoter-proximal HIF-1 binding correlates with a higher transcript abundance.

    “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 [71]

    The Results (Figure 6; page unavailable) show that HIF-1 binding sites are more promoter-proximal than HIF-2 sites. The Results section on the epigenetic landscape also reports an association between HIF-1 sites and transcriptional machinery, but the passages found do not establish that promoter-proximal HIF-1 binding correlates with higher transcript abundance. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

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Authors
Smythies, J. A., Sun, M., Masson, N., Salama, R., Simpson, P. D., Murray, E., Neumann, V., Cockman, M. E., Choudhry, H., Ratcliffe, P. J., & Mole, D. R.
Affiliations
  • University of Oxford (GB)
  • The Francis Crick Institute (GB)
  • King Abdulaziz University (SA)
Corresponding author
  • Ratcliffe, Peter J
  • Mole, David R
ORCID
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2018-11-14
Volume
20
Issue
1
ISSN
  • 1469-221X (ISSN-L)
  • 1469-3178
DOI
10.15252/embr.201846401
PMC
PMC6322389
OpenAlex
W2901273371
Cited by
195
References
53
Citations by year
2026: 14 · 2025: 26 · 2024: 19 · 2023: 26 · 2022: 38 · 2021: 24 · 2020: 31 · 2019: 17
FWCI
5.44
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Reports (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • The Francis Crick Institute (cc-by)
Funders
  • Cancer Research UK (A416016, FC001501)
  • DH | National Institute for Health Research (NIHR‐RP‐2016‐06‐004)
  • The Deanship of Scientific Research, KAU, Ministry of High Education for Saudi Arabia
  • Wellcome Trust (088182/Z/09/Z, 078333/Z/05/Z, WT091857MA, 203141/Z/16/Z, FC001501)
  • Ludwig Institute for Cancer Research
  • UK Medical Research Council (FC001501)
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, HIF-1α, HIF-2α, DNA binding specificity, transcription factor binding sites, hypoxia, cell type-specific binding, transcriptional regulation
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Cell Line, Chromatin, DNA, DNA-Binding Proteins, Gene Expression Regulation, Humans, Promoter Regions, Genetic, Transcription, Genetic, Cell Hypoxia, Protein Isoforms, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit, Epigenomics

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