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β-globin disorders such as sickle cell disease and β-thalassemia arise from defects in adult β-globin production.Induction of fetal γ-globin reduces morbidity of the diseases,but mediations currently available to induce γ-globin are antineoplastic agents that exhibit limited beneficial effects accompanied by cytotoxic and potential carcinogenic effects.Nuclear receptors TR2 and TR4, which are repressors for the fetal γ-globin gene, physically interact with lysine-specific histone demethylase 1 (LSD1) that confers epigenetic gene silencing by demethylating histone H3 lysine 4.Here we show that LSD 1 inhibition either by a monoamine oxidase inhibitor, tranylcypromine, or by RNA interference in human erythroid cells and in β-type globin transgenic mice leads to induction of human γ-globin gene expression, demonstrating a critical role for LSD 1 in γ-globin silencing in adults.This study indicates that LSD1 can be a novel target for γ-globin-inducing therapeutics, and that tranylcypromine may serve as a lead compound for developing such therapeutics.