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

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

doi:10.3324/haematol.2019.241224

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

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^*

^*Corresponding author for this work

Comprehensive Cancer Centre

Research output: Contribution to journal › Article › peer-review

6 Citations (Scopus)

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.

Original language	English
Pages (from-to)	474-482
Number of pages	9
Journal	Haematologica
Volume	106
Issue number	2
DOIs	https://doi.org/10.3324/haematol.2019.241224
Publication status	Published - Feb 2021

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Fugazza, C., Barbarani, G., Elangovan, S., Marini, M. G., Giolitto, S., Font-Monclus, I., Marongiu, M. F., Manunza, L., Strouboulis, J., Cantù, C., Gasparri, F., Barabino, S. M. L., Nakamura, Y., Ottolenghi, S., Moi, P., & Ronchi, A. E. (2021). The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene. Haematologica, 106(2), 474-482. https://doi.org/10.3324/haematol.2019.241224

@article{4e04c0ac5d664999a79f9f165e6cf25b,

title = "The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene",

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.",

author = "Cristina Fugazza and Gloria Barbarani and Sudharshan Elangovan and Marini, {Maria Giuseppina} and Serena Giolitto and Isaura Font-Monclus and Marongiu, {Maria Franca} and Laura Manunza and John Strouboulis and Claudio Cant{\`u} and Fabio Gasparri and Barabino, {Silvia M.L.} and Yukio Nakamura and Sergio Ottolenghi and Paolo Moi and Ronchi, {Antonella Ellena}",

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: {\textcopyright} 2021 Ferrata Storti Foundation Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = feb,

doi = "10.3324/haematol.2019.241224",

language = "English",

volume = "106",

pages = "474--482",

journal = "Haematologica",

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Fugazza, C, Barbarani, G, Elangovan, S, Marini, MG, Giolitto, S, Font-Monclus, I, Marongiu, MF, Manunza, L, Strouboulis, J, Cantù, C, Gasparri, F, Barabino, SML, Nakamura, Y, Ottolenghi, S, Moi, P & Ronchi, AE 2021, 'The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene', Haematologica, vol. 106, no. 2, pp. 474-482. https://doi.org/10.3324/haematol.2019.241224

TY - JOUR

T1 - The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene

AU - Fugazza, Cristina

AU - Barbarani, Gloria

AU - Elangovan, Sudharshan

AU - Marini, Maria Giuseppina

AU - Giolitto, Serena

AU - Font-Monclus, Isaura

AU - Marongiu, Maria Franca

AU - Manunza, Laura

AU - Strouboulis, John

AU - Cantù, Claudio

AU - Gasparri, Fabio

AU - Barabino, Silvia M.L.

AU - Nakamura, Yukio

AU - Ottolenghi, Sergio

AU - Moi, Paolo

AU - Ronchi, Antonella Ellena

N1 - 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.

PY - 2021/2

Y1 - 2021/2

N2 - 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.

AB - 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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U2 - 10.3324/haematol.2019.241224

DO - 10.3324/haematol.2019.241224

M3 - Article

C2 - 32107331

AN - SCOPUS:85100694985

SN - 0390-6078

VL - 106

SP - 474

EP - 482

JO - Haematologica

JF - Haematologica

IS - 2

ER -

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

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