title: MicroRNA-130a is up-regulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription.
abstract: Systemic iron balance is controlled by the liver peptide hormone hepcidin, which is transcriptionally regulated by the bone morphogenetic protein (BMP)-SMAD pathway. In iron deficiency, liver BMP-SMAD signaling and hepcidin are suppressed as a compensatory mechanism to increase iron availability. MicroRNAs are small regulatory RNAs that have an increasingly recognized role in many biologic processes but are only recently implicated in iron homeostasis regulation. Here, we demonstrate that liver expression of the microRNA miR-130a is up-regulated by iron deficiency in mice. We identify the BMP6-SMAD signaling pathway as a functional target of miR-130a in hepatoma-derived Hep3B cells. Although the TGF-β/BMP common mediator SMAD4 was previously reported to be an miR-130a target to inhibit TGF-β signaling, we do not confirm SMAD4 as an miR-130a target in our biologic system. Instead, we determine that the BMP type I receptor ALK2 is a novel target of miR-130a and that miR-130a binds to two specific sites in the 3'-untranslated region to reduce ALK2 mRNA stability. Moreover, we show in mice that the increased liver miR-130a during iron deficiency is associated with reduced liver Alk2 mRNA levels. Finally, we demonstrate that down-regulation of ALK2 by miR-130a has a functional effect to inhibit BMP6-induced hepcidin transcription in Hep3B cells. Our data suggest that iron deficiency increases liver miR-130a, which, by targeting ALK2, may contribute to reduce BMP-SMAD signaling, suppress hepcidin synthesis, and thereby promote iron availability.
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Zumbrennen-Bullough
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Qifang
authors.initials: Q
authors.lastname: Wu
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Core
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Susanna
authors.initials: S
authors.lastname: Canali
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Igor
authors.initials: I
authors.lastname: Theurl
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Delphine
authors.initials: D
authors.lastname: Meynard
authors.affiliation: From the Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 babitt.jodie@mgh.harvard.edu.
authors.forename: Jodie L
authors.initials: JL
authors.lastname: Babitt
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D055418:Bone Morphogenetic Protein 6 / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D005260:Female; D064451:Hepcidins / Q000235:genetics*; D006801:Humans; D000090463:Iron Deficiencies; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; D055418:Bone Morphogenetic Protein 6; D017931:DNA Primers; D064451:Hepcidins; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: ALK2; Activin A Receptor, Type I (ACVR1); Bone Morphogenetic Protein (BMP); Hepcidin; Iron Metabolism; MicroRNA (miRNA); SMAD Transcription Factor; SMAD4; Signal Transduction; miR-130a