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.

Fugazza, C., Barbarani, G., Elangovan, S., Marini, M., Giolitto, S., Font-Monclus, I., et al. (2021). The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene. HAEMATOLOGICA, 106(2), 474-482 [10.3324/haematol.2019.241224].

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

Fugazza, Cristina;Barbarani, Gloria;Elangovan, Sudharshan;Font-Monclus, Isaura;Cantù, Claudio;Gasparri, Fabio;Barabino, Silvia M L;Ottolenghi, Sergio;Ronchi, Antonella Ellena
2021

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.
Articolo in rivista - Articolo scientifico
Hemoglobinopathies; Red Cells; Thalassemia; transcription factors
English
27-feb-2020
2021
106
2
474
482
open
Fugazza, C., Barbarani, G., Elangovan, S., Marini, M., Giolitto, S., Font-Monclus, I., et al. (2021). The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene. HAEMATOLOGICA, 106(2), 474-482 [10.3324/haematol.2019.241224].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/268633
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