Pasricha Sant-Rayn, Lim Pei Jin, Duarte Tiago L, Casu Carla, Oosterhuis Dorenda, Mleczko-Sanecka Katarzyna, Suciu Maria, Da Silva Ana Rita, Al-Hourani Kinda, Arezes João, McHugh Kirsty, Gooding Sarah, Frost Joe N, Wray Katherine, Santos Ana, Porto Graça, Repapi Emmanouela, Gray Nicki, Draper Simon J, Ashley Neil, Soilleux Elizabeth, Olinga Peter, Muckenthaler Martina U, Hughes Jim R, Rivella Stefano, Milne Thomas A, Armitage Andrew E, Drakesmith Hal
MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Department of Medicine, The Royal Melbourne Hospital, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, 3010, Australia.
Nat Commun. 2017 Sep 1;8(1):403. doi: 10.1038/s41467-017-00500-z.
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.
铁调素调节全身铁稳态。铁调素表达的抑制在缺铁和红细胞生成增加时生理发生，但在地中海贫血和血色素沉着症中是病理性的。我们在此表明，表观遗传事件调控铁调素表达。在体内，红细胞生成和缺铁分别通过依赖和不依赖红细胞铁调素的机制抑制铁调素，但两者均涉及铁调素基因座上H3K9ac和H3K4me3的可逆性缺失。在体外，泛组蛋白去乙酰化酶抑制可提高铁调素表达，并且在体内维持铁调素相关染色质上的H3K9ac，并消除促红细胞生成素、缺铁、地中海贫血和血色素沉着症对铁调素的抑制作用。组蛋白去乙酰化酶3及其辅因子NCOR1调节铁调素；组蛋白去乙酰化酶3结合铁调素基因座上的染色质，并且组蛋白去乙酰化酶3敲低可抵消红细胞铁调素或抑制骨形态发生蛋白信号传导所诱导对铁调素的抑制作用。在缺铁小鼠中，组蛋白去乙酰化酶3抑制剂RGFP966可增加铁调素，并且RNA测序证实铁调素是该药物在体内差异调节最为显著的基因之一。我们得出结论，铁调素表达的抑制涉及组蛋白去乙酰化酶3的表观遗传调控。铁调素通过抑制肠道铁吸收和铁再循环来控制全身铁水平。在此，帕斯里查等人证明，在红细胞生成和缺铁过程中，铁调素 - 染色质基因座均显示出HDAC3介导的可逆表观遗传修饰。
