TY - JOUR AU - Cristina Fugazza, AU - Gloria Barbarani, AU - Sudharshan Elangovan, AU - Maria Giuseppina Marini, AU - Serena Giolitto, AU - Isaura Font-Monclus, AU - Maria Franca Marongiu, AU - Laura Manunza, AU - John Strouboulis, AU - Claudio Cantù, AU - Fabio Gasparri, AU - Silvia M.L. Barabino, AU - Yukio Nakamura, AU - Sergio Ottolenghi, AU - Paolo Moi, AU - Antonella Ellena Ronchi, PY - 2021/02/01 Y2 - 2024/03/28 TI - The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene JF - Haematologica JA - haematol VL - 106 IS - 2 SE - Articles DO - 10.3324/haematol.2019.241224 UR - https://haematologica.org/article/view/9675 SP - 474-482 AB - The human fetal γ-globin gene is repressed in the adult stage through complex regulatory mechanisms involving transcription factors and epigenetic modifiers. Reversing γ-globin repression, or maintaining its expression by manipulating regulatory mechanisms, has become a major clinical goal in the treatment of β-hemoglobinopathies. Here, we identify the orphan nuclear receptor Coup-TFII (NR2F2/ARP-1) as an embryonic/fetal stage activator of γ-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 β039 thalassemic patients) Coup-TFII activates the embryonic/fetal globins genes, overcoming the repression imposed by the adult erythroid environment. Conversely, the knock-out of Coup-TFII increases the β/γ+β globin ratio. Molecular analysis indicates that Coup-TFII binds in vivo to the β-locus and contributes to its conformation. Overall, our data identify Coup-TFII as a specific activator of the γ-globin gene. ER -