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Nat Commun. 2017 Sep 1;8(1):403. doi: 10.1038/s41467-017-00500-z.

Hepcidin is regulated by promoter-associated histone acetylation and HDAC3.

Author information

1
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK. sant-rayn.pasricha@ndm.ox.ac.uk.
2
Department of Medicine, The Royal Melbourne Hospital, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, 3010, Australia. sant-rayn.pasricha@ndm.ox.ac.uk.
3
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
4
Instituto de Investigação e Inovação em Saúde and IBMC-Instituto de Biologia Molecular e Celular, University of Porto, 4200-135, Porto, Portugal.
5
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, 19104, USA.
6
Pharmaceutical Technology and Biopharmacy, Department of Pharmacy, University of Groningen, 9700-AD, Groningen, The Netherlands.
7
Department of Pediatric Hematology, Oncology and Immunology, University of Heidelberg; and Molecular Medicine Partnership Unit, Heidelberg, 69117, Germany.
8
International Institute of Molecular and Cell Biology, 02-109, Warsaw, Poland.
9
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
10
Jenner Institute, University of Oxford, Old Road Campus Research Building, Oxford, OX3 7DQ, UK.
11
ICBAS-Instituto de Ciências Biomédicas Abel Salazar, University of Porto Portugal, 4050-313, Porto, Portugal.
12
Computational Biology Research Group, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
13
Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford University, Oxford, OX3 9DU, UK.
14
Division of Cellular and Molecular Pathology, Department of Pathology, Cambridge University, Cambridge, CB2 0QQ, UK.
15
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK. alexander.drakesmith@imm.ox.ac.uk.

Abstract

Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency and increased erythropoiesis but is pathologic in thalassemia and hemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and iron deficiency suppress hepcidin via erythroferrone-dependent and -independent mechanisms, respectively, in vivo, but both involve reversible loss of H3K9ac and H3K4me3 at the hepcidin locus. In vitro, pan-histone deacetylase inhibition elevates hepcidin expression, and in vivo maintains H3K9ac at hepcidin-associated chromatin and abrogates hepcidin suppression by erythropoietin, iron deficiency, thalassemia, and hemochromatosis. Histone deacetylase 3 and its cofactor NCOR1 regulate hepcidin; histone deacetylase 3 binds chromatin at the hepcidin locus, and histone deacetylase 3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting bone morphogenetic protein signaling. In iron deficient mice, the histone deacetylase 3 inhibitor RGFP966 increases hepcidin, and RNA sequencing confirms hepcidin is one of the genes most differentially regulated by this drug in vivo. We conclude that suppression of hepcidin expression involves epigenetic regulation by histone deacetylase 3.Hepcidin controls systemic iron levels by inhibiting intestinal iron absorption and iron recycling. Here, Pasricha et al. demonstrate that the hepcidin-chromatin locus displays HDAC3-mediated reversible epigenetic modifications during both erythropoiesis and iron deficiency.

PMID:
28864822
PMCID:
PMC5581335
DOI:
10.1038/s41467-017-00500-z
[Indexed for MEDLINE]
Free PMC Article

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