Browsing by Author "Duarte, T."
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- Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosisPublication . Duarte, T.; Caldas, C.; Santos, A.; Silva-Gomes, S.; Santos-Gonçalves, A.; Martins, M.; Porto, G.; Lopes, J.In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe(-/-) mice (an established model of human HFE-hemochromatosis).
- Hepcidin is regulated by promoter-associated histone acetylation and HDAC3Publication . 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.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.