The Coup-TFII orphan nuclear receptor is an activator of the gamma-globin gene

The human fetal gamma-globin gene is repressed in adulthood through complex regulatory mechanisms involving transcription factors and epigenetic modifiers. Reversing gamma-globin repression, or maintaining its expression by manipulating regulatory mechanisms, has become a major clinical goal in the treatment of beta-hemoglobinopathies. Here we identify the orphan nuclear receptor Coup-TFII (NR2F2/ARP1) as an embryonic/fetal stage activator of gamma-globin expression. We show that Coup-TFII is expressed in early erythropoiesis of yolk sac origin, together with embryonic/fetal globins. When overexpressed in adult cells (including peripheral blood cells from human healthy donors and beta degrees 39 thalassemic patients) Coup-TFII activates the embryonic/fetal globin genes, overcoming the repression imposed by the adult erythroid environment. Conversely, the knockout of Coup-TFII increases the beta/gamma+beta globin ratio. Molecular analysis indicates that Coup-TFII binds in vivo to the beta-locus and contributes to its three-dimensional conformation. Overall, our data identify Coup-TFII as a specific activator of the gamma-globin gene.