Abstract
Enhanced fetal γ-globin synthesis alleviates symptoms of β-globinopathies such as sickle cell disease and β-thalassemia, but current γ-globin-inducing drugs offer limited beneficial effects. We show here that lysine-specific demethylase 1 (LSD1) inhibition by RNAi in human erythroid cells or by the monoamine oxidase inhibitor tranylcypromine in human erythroid cells or β-type globin-transgenic mice enhances γ-globin expression. LSD1 is thus a promising therapeutic target for γ-globin induction, and tranylcypromine may serve as a lead compound for the development of a new γ-globin inducer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anemia, Sickle Cell / genetics
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Anemia, Sickle Cell / therapy
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Animals
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Cell Differentiation
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Cells, Cultured
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Erythroid Cells / drug effects
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Erythroid Cells / metabolism
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Fetal Hemoglobin / biosynthesis*
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Histone Demethylases / antagonists & inhibitors*
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Humans
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Mice
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Mice, Transgenic
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Molecular Targeted Therapy
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Monoamine Oxidase Inhibitors / pharmacology*
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Nuclear Receptor Subfamily 2, Group C, Member 1 / metabolism
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Promoter Regions, Genetic
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RNA Interference
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RNA, Small Interfering
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Receptors, Steroid / metabolism
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Receptors, Thyroid Hormone / metabolism
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Tranylcypromine / pharmacology*
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beta-Globins / genetics
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beta-Thalassemia / genetics
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beta-Thalassemia / therapy
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gamma-Globins / biosynthesis
Substances
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Monoamine Oxidase Inhibitors
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NR2C2 protein, human
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Nuclear Receptor Subfamily 2, Group C, Member 1
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RNA, Small Interfering
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Receptors, Steroid
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Receptors, Thyroid Hormone
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beta-Globins
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gamma-Globins
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Tranylcypromine
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Fetal Hemoglobin
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Histone Demethylases
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KDM1A protein, human