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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.

Original publication




Journal article


Cellular and molecular life sciences : CMLS

Publication Date





3627 - 3642


Oulu Center for Cell-Matrix Research, University of Oulu, PO Box 5400, 90014, Oulu, Finland.


Cell Line, Tumor, Chromatin, Humans, C-Reactive Protein, Serum Amyloid P-Component, Erythropoietin, Protein Isoforms, Repressor Proteins, RNA, Small Interfering, Cell Hypoxia, RNA Interference, RNA Splicing, Protein Binding, Dimerization, Apoptosis Regulatory Proteins, Glucose Transporter Type 1, Promoter Regions, Genetic, Transcriptional Activation, Bone Morphogenetic Protein 6