Hepcidin is regulated by promoter-associated histone acetylation and HDAC3

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