University of Oulu

Tolonen, J., Heikkilä, M., Malinen, M. et al. A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin. Cell. Mol. Life Sci. 77, 3627–3642 (2020).

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

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Author: Tolonen, Jussi‑Pekka1,2; Heikkilä, Minna1,2; Malinen, Marjo3;
Organizations: 1Oulu Center for Cell–Matrix Research, University of Oulu, PO Box 5400, 90014 Oulu, Finland
2Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014 Oulu, Finland
3Department of Environmental and Biological Sciences, University of Eastern Finland, 80100 Joensuu, Finland
4Institute of Biomedicine, University of Eastern Finland, 70211 Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.1 MB)
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Language: English
Published: Springer Nature, 2020
Publish Date: 2020-02-21


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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Series: Cellular and molecular life sciences
ISSN: 1420-682X
ISSN-E: 1420-9071
ISSN-L: 1420-682X
Volume: 77
Pages: 3627 - 3642
DOI: 10.1007/s00018-019-03387-9
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: Open access funding provided by University of Oulu including Oulu University Hospital. This study was supported by the Academy of Finland Project Grant 296498, the Academy of Finland Center of Excellence 2012–2017 Grant 251314, the Sigrid Jusélius Foundation, the Jane and Aatos Erkko Foundation, the Maud Kuistila Memorial Foundation, and FibroGen Inc.
Academy of Finland Grant Number: 296498
Detailed Information: 296498 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright information: © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.