Journal article
Hepcidin is regulated by promoter-associated histone acetylation and HDAC3
- Abstract:
- Hepcidin regulates systemic iron homeostasis. Suppression of hepcidin expression occurs physiologically in iron deficiency (ID) and increased erythropoiesis but is pathologic in thalassaemia and haemochromatosis. Here we show that epigenetic events govern hepcidin expression. Erythropoiesis and ID 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, ID, thalassaemia and haemochromatosis. HDAC3 and its cofactor NCOR1 regulate hepcidin; HDAC3 binds chromatin at the hepcidin locus, and HDAC3 knockdown counteracts hepcidin suppression induced either by erythroferrone or by inhibiting BMP signaling. In ID mice, the HDAC3 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 HDAC3.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 1.5MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-017-00500-z
Authors
+ Wellcome Trust
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- Funding agency for:
- Draper, S
- Ashley, N
- Grant:
- 106917/Z/15/Z
- MR/M00919X/1
+ Medical Research Council
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- Funding agency for:
- Lim, P
- Al-Hourani, K
- Wray, K
- Ashley, N
- Armitage, A
- Drakesmith, A
- Grant:
- MR/M00919X/1
- Publisher:
- Nature Publishing Group
- Journal:
- Nature Communications More from this journal
- Volume:
- 8
- Pages:
- 403
- Publication date:
- 2017-09-01
- Acceptance date:
- 2017-07-04
- DOI:
- EISSN:
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2041-1723
- Keywords:
- Pubs id:
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pubs:702961
- UUID:
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uuid:1cc91d22-8743-435b-97b0-b17588268d95
- Local pid:
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pubs:702961
- Source identifiers:
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702961
- Deposit date:
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2017-07-04
- ARK identifier:
Terms of use
- Copyright holder:
- Pasricha et al
- Copyright date:
- 2017
- Notes:
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© The Author(s) 2017. This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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