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Cited by 37Cancer, Hypoxia, and MetabolismGenomics and Chromatin DynamicsAngiogenesis and VEGF in Cancer

Functional and HRE motifs count analysis of induction of selected hypoxia-responsive genes by HIF-1 and HIF-2 in human umbilical endothelial cells

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Cabaj, Aleksandra, Moszyńska, Adrianna, Charzyńska, Agata, Bartoszewski, Rafał, Dąbrowski, Michał·2022·Cellular Signalling
DOI 10.1016/j.cellsig.2021.110209
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Abstract

We analyzed the effects of selective knockdown of either HIF-1α or HIF-2α on the transcriptional response to hypoxia of human umbilical endothelial cells at two time-points (2 h and 8 h) of hypoxia. We focused on 13 previously identified hypoxia-responsive genes, pre-selected to have different activation kinetics and different proportions of HRE motifs annotated to either HIF-1 or HIF-2 in open promoters - open chromatin DNase-hypersensitive sites (DHS) regions within ±1 kb of the gene start. We report that genes activated by both HIF-1 and 2 tend to be activated earlier than genes activated by HIF-1 only, which, in turn, tend to be activated earlier than genes activated by HIF-2 only. Moreover, for the 13 analyzed genes, we found that the effect of silencing HIF1A on the gene induction by hypoxia is greater for the genes with more HRE motifs annotated to HIF-1 in their promoter open chromatin DHS regions within ±1 kb and also within ±10 kb of the gene start. We corroborated and extended this finding by showing that among 232 genes previously identified as activated by hypoxia, the genes with ChIP-seq peak(s) for HIF-1α within a ±10 kb flank of the gene start contain more HRE motifs annotated to HIF-1 in the DHS regions within this flank than the genes with no ChIP-seq peaks. Also in the whole genome, the DHS regions intersecting ChIP-seq peaks for HIF-1α contain more HRE motifs annotated to HIF-1 than the DHS regions not intersecting the ChIP-seq peaks. This suggests a mechanism, by which higher promoter content of HRE motifs in DHS regions increases HIF-1 binding, which in turn increases gene induction by hypoxia.

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  • Diversity in HIF complex composition contributes to cell type-specific hypoxic transcriptional responses.

    “This diversity in HIF complex composition contributes to cell type–specific hypoxic transcriptional responses”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [66]

    The Introduction describes HIF-1 and HIF-2 as complexes with different alpha subunits and distinct binding preferences. The Discussion reports that they regulate different hypoxia-responsive genes in human umbilical endothelial cells, but it does not establish that variation in complex composition causes differences in transcriptional responses between cell types; it notes substantial agreement with findings in other cell types. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The global architecture of HIF-1- and HIF-2-dependent target gene networks remains largely conserved across different cell types.

    “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 [66]

    The Discussion reports agreement between HUVECs and other cell types on which HIF regulates seven selected genes. It also says the distribution of HIF-1 and HIF-2 binding sites remains similar across cell types. These observations support some cross-cell-type conservation, but the paper does not establish that the global architecture of HIF-dependent target-gene networks is conserved. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Cabaj, A., Moszyńska, A., Charzyńska, A., Bartoszewski, R., & Dąbrowski, M.
Affiliations
  • Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
  • Gdańsk Medical University (PL)
Corresponding author
Dąbrowski, Michał
ORCID
Venue
Cellular Signalling
Publisher
Elsevier BV
Published
2022-02
Volume
90
Pages
110209
ISSN
0898-6568 (ISSN-L)
DOI
10.1016/j.cellsig.2021.110209
OpenAlex
W4200182500
Cited by
37
References
57
Citations by year
2026: 8 · 2025: 7 · 2024: 11 · 2023: 8 · 2022: 2 · 2021: 1
FWCI
2.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular Signalling (publishedVersion, cc-by)
  • PubMed (publishedVersion)
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 › Angiogenesis and VEGF in Cancer
Keywords
hypoxia-responsive genes, HIF-1α, HIF-2α, hypoxia-inducible factor, hypoxia response element, human umbilical vein endothelial cells, transcriptional regulation, DNase I hypersensitive sites, open chromatin, HIF-1α knockdown
MeSH terms
Hypoxia, Humans, Promoter Regions, Genetic, Cell Hypoxia, Genome, Response Elements, Endothelial Cells, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit

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