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Hepcidin is regulated by promoter-associated histone acetylation and HDAC3

Pasricha, S-R., Lim, P. J., Duarte, T. L., Casu, C., Oosterhuis, D., Mleczko-Sanecka, K., Suciu, M., Da Silva, A. R., Al-Hourani, K., Arezes, J., McHugh, K., Gooding, S., Frost, J. N., Wray, K., Santos, A., Porto, G., Repapi, E., Gray, N., Draper, S. J., Ashley, N., Soilleux, E., Olinga, P., Muckenthaler, M. U., Hughes, J. R., Rivella, S., Milne, T. A., Armitage, A. E. & Drakesmith, H. 1-Sep-2017 In : Nature Communications. 8, 15 p., 403

Research output: Scientific - peer-reviewArticle

Documents

DOI

  • 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
  • Hal Drakesmith

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.

Original languageEnglish
Article number403
Number of pages15
JournalNature Communications
Volume8
StatePublished - 1-Sep-2017

    Keywords

  • Journal Article

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