Functional And Mechanistic Study Of HDAC1 Regulating Iron Homeostasis

Iron metabolism is pivotal for human health.Hepcidin is known as the key hormone which maintains iron homeostasis.Hepcidin regulation has been the hot-spot in iron metabolism research area.In recent years,epigenetic modulators,especially histone deacetylases(HDACs)were found to involve Hepcidin regulation.However,the exact HD AC member and detailed mechanism are hitherto unknown.In our study,we applied HDAC related compound screen to identify Entinostat as a potent compound to activate Hepcidin transcription.We further confirmed the mechanism and the effect in vivo.Entinostat,the clinical used histone deacetylase 1(HDAC 1)inhibitor,was identified as the most potent Hepcidin agonist.Consistently,Hdac1 hepatocytes-specific deficient mice also presented higher Hepcidin levels than wild-type controls.Notably,the long-term treatment of Hfe-/-mice with Entinostat significantly alleviated iron overload through upregulating Hepcidin transcription.In contrast,Entinostat showed no effect on Hepcidin expression and iron levels in Smad4fl/fl Alb-Cre+ mice.Further mechanistic studies revealed that HDAC1 suppressed Hepcidin expression through interacting with SMAD4 and disrupting the binding of SMAD4 on Hepcidin promoter at the BMP responsive elements rather than deacetylation of SMAD4 or histone-H3 on the Hepcidin promoter.In this project,we demonstrated the underlying mechanism of HDAC 1-Hepcidin axis by employing biochemistry experiments.In the meantime,we validated the ameliorative effect of Entinostat on iron overload phenotype in hemochromatosis mice model-Hfe-/-mice.We provided a novel therapeutic target for iron disorder diseases.