COUP-TFII ORPHAN NUCLEAR RECEPTOR IS AN ACTIVATOR OF FETAL GLOBIN GENES IN ADULT ERYTHROID CELLS

The maintenance or reactivation of the expression of the fetal ?-globin gene in adult patients affected by Sickle Cell Disease and ?-thalassemia is an important clinical goal. Here we report a novel role of the orphan nuclear receptor Coup-TFII (NR2F2/ARP-1) as an activator of ?-globin in different erythroid cells systems. In mouse, Coup-TFII is expressed in early erythropoiesis of yolk sac origin, together with embryonic/fetal globins. Importantly, Coup-TFII overexpression activates the embryonic/fetal globins genes when expressed in adult cells (mouse E13.5 fetal liver proerythroblasts and human peripheral blood cultures from healthy donors and ?039 thalassemic patients), where it overcomes the repression imposed by the adult erythroid environment. Conversely, the knock-out of Coup-TFII in ?- globin K562 expressing cells (?-K562) results in an increase of the ?/(?+?) ratio. Overall, our data identify Coup-TFII as a yolk sac transcription factor capable of activating embryonic/fetal globins genes in adult cells.