title: miR-429 regulates the transition between Hypoxia-Inducible Factor (HIF)1A and HIF3A expression in human endothelial cells.
abstract: Hypoxia-inducible factors (HIF) are heterodimeric transcription factors that allow cells to adapt and survive during hypoxia. Regulation of HIF1A and HIF2A mRNA is well characterized, whereas HIF3A mRNA regulation and function are less clear. Using RNA-Seq analysis of primary human umbilical vein endothelial cells, we found two isoforms of HIF3A were expressed, HIF3A2 and HIF3A3. Comparing HIF3A expression profiles to HIF1A mRNA during 48 hours of hypoxia revealed that HIF1A message peaked at 4 hours, whereas HIF3A expression increased while HIF1A was decreasing. Given that HIF1A mRNA is regulated by miR-429, we tested miR-429 effects on both HIF3A isoforms and found that they too were regulated by miR-429. Analysis of a HIF-3 target, DNA-damage-inducible transcript 4, a key survival gene, indicated that DDIT4 mRNA is induced by HIF-3 and negatively regulated by miR-429 through miR-429's actions on HIF3A message. This provides a compelling model for how hypoxia-induced miR-429 regulates the switch between HIF-1 adaptive responses to HIF-3 survival responses by rapidly decreasing HIF1A levels while simultaneously slowing the progression of HIF3A expression until the miR-429 levels drop below normoxic levels. Since HIF-1 drives HIF3A and miR-429 expression, this establishes a regulatory network in which miR-429 plays a pivotal role.
authors.affiliation: Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Janaszak-Jasiecka
authors.affiliation: Department of Inorganic Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Bartoszewska
authors.affiliation: Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Kochan
authors.affiliation: Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Piotrowski
authors.affiliation: Department of Medical Laboratory Diagnostics, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Kalinowski
authors.affiliation: Department of Inorganic Chemistry, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kamysz
authors.affiliation: Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Renata J
authors.initials: RJ
authors.lastname: Ochocka
authors.affiliation: Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Gdansk, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Bartoszewski
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Collawn
mesh_terms: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D035683:MicroRNAs / Q000378:metabolism*; D012097:Repressor Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D012097:Repressor Proteins; C497442:HIF1A protein, human; C116973:HIF3A protein, human; C546363:MIRN429 microRNA, human