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

Authors
  • Tolonen, Jussi-Pekka1, 1
  • Heikkilä, Minna1, 1
  • Malinen, Marjo2
  • Lee, Hang-Mao1
  • Palvimo, Jorma J.2
  • Wei, Gong-Hong1
  • Myllyharju, Johanna1, 1
  • 1 University of Oulu,
  • 2 University of Eastern Finland,
Type
Published Article
Journal
Cellular and Molecular Life Sciences
Publisher
Springer-Verlag
Publication Date
Nov 25, 2019
Volume
77
Issue
18
Pages
3627–3642
Identifiers
DOI: 10.1007/s00018-019-03387-9
PMID: 31768607
PMCID: PMC7452874
Source
PubMed Central
Keywords
License
Unknown

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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