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dc.contributor.authorPasricha, Sant-Rayn
dc.contributor.authorLim, Pei Jin
dc.contributor.authorDuarte, Tiago L
dc.contributor.authorCasu, Carla
dc.contributor.authorOosterhuis, Dorenda
dc.contributor.authorMleczko-Sanecka, Katarzyna
dc.contributor.authorSuciu, Maria
dc.contributor.authorDa Silva, Ana Rita
dc.contributor.authorAl-Hourani, Kinda
dc.contributor.authorArezes, João
dc.contributor.authorMcHugh, Kirsty
dc.contributor.authorGooding, Sarah
dc.contributor.authorFrost, Joe N
dc.contributor.authorWray, Katherine
dc.contributor.authorSantos, Ana
dc.contributor.authorPorto, Graça
dc.contributor.authorRepapi, Emmanouela
dc.contributor.authorGray, Nicki
dc.contributor.authorDraper, Simon J
dc.contributor.authorAshley, Neil
dc.contributor.authorSoilleux, Elizabeth
dc.contributor.authorOlinga, Peter
dc.contributor.authorMuckenthaler, Martina U
dc.contributor.authorHughes, Jim R
dc.contributor.authorRivella, Stefano
dc.contributor.authorMilne, Thomas A
dc.contributor.authorArmitage, Andrew E
dc.contributor.authorDrakesmith, Hal
dc.date.accessioned2018-12-18T00:33:04Z
dc.date.available2018-12-18T00:33:04Z
dc.date.issued2017-09-01
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/287119
dc.description.abstractHepcidin 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.
dc.format.mediumElectronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectHumans
dc.subjectIron
dc.subjectHistone Deacetylases
dc.subjectErythropoietin
dc.subjectHistones
dc.subjectGene Expression Regulation
dc.subjectEpigenesis, Genetic
dc.subjectAmino Acid Motifs
dc.subjectAcetylation
dc.subjectMale
dc.subjectPromoter Regions, Genetic
dc.subjectHepcidins
dc.titleHepcidin is regulated by promoter-associated histone acetylation and HDAC3.
dc.typeArticle
prism.issueIdentifier1
prism.publicationDate2017
prism.publicationNameNat Commun
prism.startingPage403
prism.volume8
dc.identifier.doi10.17863/CAM.34428
dcterms.dateAccepted2017-07-04
rioxxterms.versionofrecord10.1038/s41467-017-00500-z
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-09
dc.contributor.orcidPasricha, Sant-Rayn [0000-0002-5502-0434]
dc.contributor.orcidDuarte, Tiago L [0000-0002-4901-4580]
dc.contributor.orcidDraper, Simon J [0000-0002-9415-1357]
dc.contributor.orcidSoilleux, Elizabeth [0000-0002-4032-7249]
dc.contributor.orcidHughes, Jim R [0000-0002-8955-7256]
dc.contributor.orcidMilne, Thomas A [0000-0002-0413-4271]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Review
cam.issuedOnline2017-09-01


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Except where otherwise noted, this item's licence is described as Attribution 4.0 International