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

Fugazza, Cristina;Barbarani, Gloria;Elangovan, Sudharshan;Marini, Maria Giuseppina;Giolitto, Serena;Font-Monclus, Isaura;Marongiu, Maria Franca;Manunza, Laura;Strouboulis, John;Cantù, Claudio;Gasparri, Fabio;Barabino, Silvia M L;Nakamura, Yukio;Ottolenghi, Sergio;Moi, Paolo

Penultimate

;Ronchi, Antonella Ellena

2021-01-01

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Abstract

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.