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

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

Original languageEnglish
Pages (from-to)474-482
Number of pages9
JournalHaematologica
Volume106
Issue number2
DOIs
PublishedFeb 2021

Bibliographical note

Funding Information: The authors would like to thank Dr. Andrea Ditadi for help with experimental work, Fondazione Cariplo grant n. 2012.0517 for support to AR, PM and JS, the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007-2013/ under REA grant agreement n. 289611 (HEM_ID Project) for support to AR and JS and the Knut and Alice Wallenberg foundation for support to CC. Publisher Copyright: © 2021 Ferrata Storti Foundation Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

The human fetal γ-globin gene is repressed in adulthood 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 globin genes, overcoming the repression imposed by the adult erythroid environment. Conversely, the knockout 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 three-dimensional conformation. Overall, our data identify Coup-TFII as a specific activator of the γ-globin gene.

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