Hepcidin is regulated by promoter-associated histone acetylation and HDAC3.
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Authors
Lim, Pei Jin
Casu, Carla
Oosterhuis, Dorenda
Mleczko-Sanecka, Katarzyna
Suciu, Maria
Da Silva, Ana Rita
Al-Hourani, Kinda
Arezes, João
McHugh, Kirsty
Gooding, Sarah
Frost, Joe N
Wray, Katherine
Santos, Ana
Porto, Graça
Repapi, Emmanouela
Gray, Nicki
Ashley, Neil
Soilleux, Elizabeth
Olinga, Peter
Muckenthaler, Martina U
Rivella, Stefano
Armitage, Andrew E
Drakesmith, Hal
Publication Date
2017-09-01Journal Title
Nat Commun
ISSN
2041-1723
Publisher
Springer Science and Business Media LLC
Volume
8
Issue
1
Pages
403
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic
Metadata
Show full item recordCitation
Pasricha, S., Lim, P. J., Duarte, T. L., Casu, C., Oosterhuis, D., Mleczko-Sanecka, K., Suciu, M., et al. (2017). Hepcidin is regulated by promoter-associated histone acetylation and HDAC3.. Nat Commun, 8 (1), 403. https://doi.org/10.1038/s41467-017-00500-z
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.
Keywords
Acetylation, Amino Acid Motifs, Animals, Epigenesis, Genetic, Erythropoietin, Gene Expression Regulation, Hepcidins, Histone Deacetylases, Histones, Humans, Iron Deficiencies, Male, Mice, Inbred C57BL, Promoter Regions, Genetic
Identifiers
External DOI: https://doi.org/10.1038/s41467-017-00500-z
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287119
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