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Cited by 63Erythropoietin and Anemia TreatmentCancer, Hypoxia, and MetabolismHemoglobin structure and function

A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

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Tolonen, Jussi-Pekka, Heikkilä, Minna, Malinen, Marjo, Lee, Hang-Mao, Palvimo, Jorma J., Wei, Gong-Hong, Myllyharju, Johanna·2020·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-019-03387-9PMC PMC7452874
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Abstract

Hypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis with hundreds of hypoxia-inducible target genes. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered a negative regulator of the hypoxia response pathway. However, the human HIF3A mRNA is subject to complex alternative splicing. It was recently shown that the long HIF-3α variants can form αβ dimers that possess transactivation capacity. Here, we show that overexpression of the long HIF-3α2 variant induces the expression of a subset of genes, including the erythropoietin (EPO) gene, while simultaneous downregulation of all HIF-3α variants by siRNA targeting a shared HIF3A region leads to downregulation of EPO and additional genes. EPO mRNA and protein levels correlated with HIF3A silencing and HIF-3α2 overexpression. Chromatin immunoprecipitation analyses showed that HIF-3α2 binding associated with canonical hypoxia response elements in the promoter regions of EPO. Luciferase reporter assays showed that the identified HIF-3α2 chromatin-binding regions were sufficient to promote transcription by all three HIF-α isoforms. Based on these data, HIF-3α2 is a transcription activator that directly regulates EPO expression.

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  • HIF-3 shares transcriptional targets with HIF-1 and HIF-2, including EPO, GLUT1, ANGPTL4, REDD1 (DDIT4), LC3C, and SQRDL.

    “Indeed, HIF-3 shares transcriptional targets with HIF-1 and HIF-2, including EPO, GLUT1, ANGPTL4, REDD1 (DDIT4), LC3C, and SQRDL [59,101,108,112]”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [101]

    The Discussion (page unavailable) identifies all six listed genes as regulated by HIF-3 or reports studies finding their induction by HIF-3. It also says that all three HIF-α isoforms activate an EPO reporter, but it does not establish that each of the other listed genes is a shared transcriptional target of HIF-1 and HIF-2. (LLM, conf=0.82)

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Authors
Tolonen, J.-P., Heikkilä, M., Malinen, M., Lee, H.-M., Palvimo, J. J., Wei, G.-H., & Myllyharju, J.
Affiliations
  • University of Oulu (FI)
  • University of Eastern Finland (FI)
Corresponding author
Myllyharju, Johanna
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2019-11-25
Volume
77
Issue
18
Pages
3627-3642
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-019-03387-9
PMC
PMC7452874
OpenAlex
W2991330371
Cited by
63
References
6
Citations by year
2026: 8 · 2025: 5 · 2024: 11 · 2023: 14 · 2022: 11 · 2021: 9 · 2020: 5
FWCI
4.59
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular and Molecular Life Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Academy of Finland (296498, 251314)
  • Sigrid Juséliuksen Säätiö
  • Jane ja Aatos Erkon Säätiö
  • Maud Kuistilan Muistosäätiö
  • FibroGen
Topics
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
Keywords
erythropoietin, transcriptional activation, alternative splicing, hypoxia response element, oxygen homeostasis, gene expression regulation, chromatin binding
MeSH terms
Pentraxins, Serum Amyloid P-Component, C-Reactive Protein, Chromatin, Erythropoietin, Humans, Promoter Regions, Genetic, Protein Binding, Repressor Proteins, RNA Splicing, Transcriptional Activation, Cell Hypoxia, Dimerization, Protein Isoforms, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Apoptosis Regulatory Proteins, Glucose Transporter Type 1, Bone Morphogenetic Protein 6

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