Genome-wide identification of hypoxia-inducible factor-1 and -2 binding sites in hypoxic human macrophages alternatively activated by IL-10
Abstract
Macrophages (MΦ) often accumulate in hypoxic areas, where they significantly influence disease progression. Anti-inflammatory cytokines, such as IL-10, generate alternatively activated macrophages that support tumor growth. To understand how alternative activation affects the transcriptional profile of hypoxic macrophages, we globally mapped binding sites of hypoxia-inducible factor (HIF)-1α and HIF-2α in primary human monocyte-derived macrophages prestimulated with IL-10. 713 HIF-1 and 795 HIF-2 binding sites were identified under hypoxia. Pretreatment with IL-10 altered the binding pattern, with 120 new HIF-1 and 188 new HIF-2 binding sites emerging. HIF-1 binding was most prominent in promoters, while HIF-2 binding was more abundant in enhancer regions. Comparison of ChIP-seq data obtained in other cells revealed a highly cell type specific binding of HIF. In MΦ HIF binding occurred preferentially in already active enhancers or promoters. To assess the roles of HIF on gene expression, primary human macrophages were treated with siRNA against HIF-1α or HIF-2α, followed by genome-wide gene expression analysis. Comparing mRNA expression to the HIF binding profile revealed a significant enrichment of hypoxia-inducible genes previously identified by ChIP-seq. Analysis of gene expression under hypoxia alone and hypoxia/IL-10 showed the enhanced induction of a set of genes including PLOD2 and SLC2A3, while another group including KDM3A and ADM remained unaffected or was reduced b…
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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 [79]
Cites
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“Although HIFs consistently drive expression of genes involved in glycolysis, their overall DNA-binding pattern is highly context specific, varying with cell type, external stimuli, and epigenetic landscape (17, 18).”
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“Promoter-proximal HIF-1 binding correlates with a higher transcript abundance [68,71,79,82].”
- Authors
- Tausendschön, M., Rehli, M., Dehne, N., Schmidl, C., Döring, C., Hansmann, M.-L., & Brüne, B.
- Affiliations
- Goethe University Frankfurt (DE)
- University Hospital Regensburg (DE)
- Corresponding author
- Dehne, Nathalie
- Venue
- Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 1849
- Issue
- 1
- Pages
- 10-22
- ISSN
- 1874-9399 (ISSN-L)
- OpenAlex
- W2020544634
- Cited by
- 43
- References
- 8
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 5 · 2017: 5 · 2016: 4 · 2015: 3 · 2014: 1
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- hypoxia-inducible factor-1α, HIF-2α, alternative activation, IL-10, macrophages, hypoxia, enhancers, promoter, cell-type-specific transcription, HIF-1α knockdown, PLOD2, GLUT3, KDM3A, ADM, tumor-associated macrophages
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Binding Sites, Gene Expression Regulation, Humans, Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase, Macrophages, Cell Hypoxia, Genome, Human, Interleukin-10, Glucose Transporter Type 3, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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