Hepcidin is regulated by promoter-associated histone acetylation and HDAC3

Sant-Rayn Pasricha (), Pei Jin Lim, Tiago L. Duarte, Carla Casu, Dorenda Oosterhuis, Katarzyna Mleczko-Sanecka, Maria Suciu, Ana Rita Da Silva, Kinda Al-Hourani, João Arezes, Kirsty McHugh, Sarah Gooding, Joe N. Frost, Katherine Wray, Ana Santos, Graça Porto, Emmanouela Repapi, Nicki Gray, Simon J. Draper, Neil Ashley, Elizabeth Soilleux, Peter Olinga, Martina U. Muckenthaler, Jim R. Hughes, Stefano Rivella, Thomas A. Milne, Andrew E. Armitage and Hal Drakesmith ()
Additional contact information
Sant-Rayn Pasricha: University of Oxford
Pei Jin Lim: University of Oxford
Tiago L. Duarte: University of Porto
Carla Casu: Children’s Hospital of Philadelphia
Dorenda Oosterhuis: University of Groningen
Katarzyna Mleczko-Sanecka: University of Heidelberg; and Molecular Medicine Partnership Unit
Maria Suciu: University of Oxford
Ana Rita Da Silva: University of Heidelberg; and Molecular Medicine Partnership Unit
Kinda Al-Hourani: University of Oxford
João Arezes: University of Oxford
Kirsty McHugh: University of Oxford
Sarah Gooding: University of Oxford
Joe N. Frost: University of Oxford
Katherine Wray: University of Oxford
Ana Santos: University of Porto
Graça Porto: University of Porto
Emmanouela Repapi: University of Oxford, John Radcliffe Hospital
Nicki Gray: University of Oxford, John Radcliffe Hospital
Simon J. Draper: University of Oxford
Neil Ashley: University of Oxford
Elizabeth Soilleux: Oxford University
Peter Olinga: University of Groningen
Martina U. Muckenthaler: University of Heidelberg; and Molecular Medicine Partnership Unit
Jim R. Hughes: University of Oxford
Stefano Rivella: Children’s Hospital of Philadelphia
Thomas A. Milne: University of Oxford
Andrew E. Armitage: University of Oxford
Hal Drakesmith: University of Oxford

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00500-z

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