Hepcidin is regulated by promoter-associated histone acetylation and HDAC3
Autor(a) principal: | |
---|---|
Data de Publicação: | 2017 |
Outros Autores: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10400.16/2232 |
Resumo: | 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. |
id |
RCAP_fa0cbfac233d77f132b4b4327eac7dc1 |
---|---|
oai_identifier_str |
oai:repositorio.chporto.pt:10400.16/2232 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3Hepcidin 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.We 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.Nature Publishing GroupRepositório Científico do Centro Hospitalar Universitário de Santo AntónioPasricha, S.Lim, P.Duarte, T.Casu, C.Oosterhuis, D.Mleczko-Sanecka, K.Suciu, M.Da Silva, A.Al-Hourani, K.Arezes, J.McHugh, K.Gooding, S.Frost, J.Wray, K.Santos, A.Porto, G.Repapi, E.Gray, N.Draper, S.Ashley, N.Soilleux, E.Olinga, P.Muckenthaler, M.Hughes, J.Rivella, S.Milne, T.Armitage, A.Drakesmith, H.2018-08-28T11:10:40Z2017-09-012017-09-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.16/2232engNat Commun. 2017 Sep 1;8(1):4032041-172310.1038/s41467-017-00500-zinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-10-20T10:59:41Zoai:repositorio.chporto.pt:10400.16/2232Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:38:27.395900Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 |
title |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 |
spellingShingle |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 Pasricha, S. |
title_short |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 |
title_full |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 |
title_fullStr |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 |
title_full_unstemmed |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 |
title_sort |
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3 |
author |
Pasricha, S. |
author_facet |
Pasricha, S. Lim, P. Duarte, T. Casu, C. Oosterhuis, D. Mleczko-Sanecka, K. Suciu, M. Da Silva, A. Al-Hourani, K. Arezes, J. McHugh, K. Gooding, S. Frost, J. Wray, K. Santos, A. Porto, G. Repapi, E. Gray, N. Draper, S. Ashley, N. Soilleux, E. Olinga, P. Muckenthaler, M. Hughes, J. Rivella, S. Milne, T. Armitage, A. Drakesmith, H. |
author_role |
author |
author2 |
Lim, P. Duarte, T. Casu, C. Oosterhuis, D. Mleczko-Sanecka, K. Suciu, M. Da Silva, A. Al-Hourani, K. Arezes, J. McHugh, K. Gooding, S. Frost, J. Wray, K. Santos, A. Porto, G. Repapi, E. Gray, N. Draper, S. Ashley, N. Soilleux, E. Olinga, P. Muckenthaler, M. Hughes, J. Rivella, S. Milne, T. Armitage, A. Drakesmith, H. |
author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório Científico do Centro Hospitalar Universitário de Santo António |
dc.contributor.author.fl_str_mv |
Pasricha, S. Lim, P. Duarte, T. Casu, C. Oosterhuis, D. Mleczko-Sanecka, K. Suciu, M. Da Silva, A. Al-Hourani, K. Arezes, J. McHugh, K. Gooding, S. Frost, J. Wray, K. Santos, A. Porto, G. Repapi, E. Gray, N. Draper, S. Ashley, N. Soilleux, E. Olinga, P. Muckenthaler, M. Hughes, J. Rivella, S. Milne, T. Armitage, A. Drakesmith, H. |
description |
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. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017-09-01 2017-09-01T00:00:00Z 2018-08-28T11:10:40Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.16/2232 |
url |
http://hdl.handle.net/10400.16/2232 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Nat Commun. 2017 Sep 1;8(1):403 2041-1723 10.1038/s41467-017-00500-z |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Nature Publishing Group |
publisher.none.fl_str_mv |
Nature Publishing Group |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799133645712130048 |