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Hepcidin is regulated by promoter-associated histone acetylation and HDAC3

2017-09-01Journal article Open access
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dc.contributor.authorPasricha, S.
dc.contributor.authorLim, P.
dc.contributor.authorDuarte, T.
dc.contributor.authorCasu, C.
dc.contributor.authorOosterhuis, D.
dc.contributor.authorMleczko-Sanecka, K.
dc.contributor.authorSuciu, M.
dc.contributor.authorDa Silva, A.
dc.contributor.authorAl-Hourani, K.
dc.contributor.authorArezes, J.
dc.contributor.authorMcHugh, K.
dc.contributor.authorGooding, S.
dc.contributor.authorFrost, J.
dc.contributor.authorWray, K.
dc.contributor.authorSantos, A.
dc.contributor.authorPorto, G.
dc.contributor.authorRepapi, E.
dc.contributor.authorGray, N.
dc.contributor.authorDraper, S.
dc.contributor.authorAshley, N.
dc.contributor.authorSoilleux, E.
dc.contributor.authorOlinga, P.
dc.contributor.authorMuckenthaler, M.
dc.contributor.authorHughes, J.
dc.contributor.authorRivella, S.
dc.contributor.authorMilne, T.
dc.contributor.authorArmitage, A.
dc.contributor.authorDrakesmith, H.
dc.date.accessioned2018-08-28T11:10:40Z
dc.date.available2018-08-28T11:10:40Z
dc.date.issued2017-09-01
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.pt_PT
dc.description.sponsorshipWe thank Jing Jin (Jenner Institute, Oxford) for assistance with protein production. SP was supported by the NHMRC (Australia), the Haematology Society of Australia and New Zealand, The Bill and Melinda Gates Foundation, and the Cooley’s Anemia Foundation, and received training from the ASH/EHA Translational Training in Hematology Program. H.D., P.J.L., A.E.A., K.A.-H., and K.W. were supported by the Medical Research Council UK and the National Institute for Health Research Biomedical Research Centre Oxford. Production of erythroferrone and K.M. and J.A. were supported by Pfizer Ltd. C.C. and S.R. were supported by NIH-R01 DK095112 and DK090554. S.J.D. is a Jenner Investigator, a Lister Institute Research Prize Fellow and a Wellcome Trust Senior Fellow (106917/Z/15/Z). T.L.D., A.S., and G.P. were supported by Fundação para a Ciência e a Tecnologia/Ministério da Educação e Ciência and COMPETE (FCOMP-01-0124-FEDER-028447, PTDC/BIM-MET/0739/2012, SFRH/BPD/108207/2015), and by Programme NORTE 2020, under the PORTUGAL 2020 Partnership Agreement, through the FEDER (Project Norte-01-0145-FEDER-000012). D.O. was supported by ZonMw (project 11401095001). N.A. was supported by the MRC funded Oxford Consortium for Single-cell Biology (MR/M00919X/1), and the Oxford-Wellcome Trust Institutional Strategic Support Fund.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNat Commun. 2017 Sep 1;8(1):403pt_PT
dc.identifier.doi10.1038/s41467-017-00500-zpt_PT
dc.identifier.issn2041-1723
dc.identifier.urihttp://hdl.handle.net/10400.16/2232
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherNature Publishing Grouppt_PT
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-017-00500-z.pdfpt_PT
dc.titleHepcidin is regulated by promoter-associated histone acetylation and HDAC3pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/COMPETE/PTDC%2FBIM-MET%2F0739%2F2012/PT
oaire.citation.conferencePlaceEnglandpt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage403pt_PT
oaire.citation.titleNature Communicationspt_PT
oaire.citation.volume8pt_PT
oaire.fundingStreamCOMPETE
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationb31f5f4b-835a-4388-9935-818c58c78083
relation.isProjectOfPublication.latestForDiscoveryb31f5f4b-835a-4388-9935-818c58c78083

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