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Ferrata Storti Foundation
Haematologica 2021 Volume 106(2):474-482
Red Cell Biology & its Disorders
The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene
Cristina Fugazza,1* Gloria Barbarani,1* Sudharshan Elangovan,1*° Maria Giuseppina Marini,2 Serena Giolitto,1 Isaura Font-Monclus,1 Maria Franca Marongiu,2 Laura Manunza,3 John Strouboulis,4 Claudio Cantù,5 Fabio Gasparri,6 Silvia M.L. Barabino,1 Yukio Nakamura,7 Sergio Ottolenghi,1 Paolo Moi3 and Antonella Ellena Ronchi1
1Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca,
2
Milano, Italy; Istituto di Ricerca Genetica e Biomedica del Consiglio Nazionale delle
Ricerche, Cagliari, Italy; 3Dipartimento di Sanità Pubblica, Medicina Clinica e Molecolare, Università degli Studi di Cagliari, Cagliari, Italy; 4School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK; 5Wallenberg Center for Molecular Medicine, Department of Clinical and Experimental Medicine (IKE), Linköping University, Linköping, Sweden; 6Department of Biology, Nerviano Medical Sciences S.r.l., Nerviano, Milano, Italy and 7University of Tsukuba, Tsukuba, Ibaraki, Japan
*CF, GB and SE contributed equally as co-first authors.
°Present address: Genomics Division, Wipro Life Sciences Laboratory, WIPRO Limited, Bengaluru, Karnataka, India
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 main- taining 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 glo- bin 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 conforma- tion. Overall, our data identify Coup-TFII as a specific activator of the γ- globin gene.
Introduction
In mammals, the developmental regulation of erythropoiesis ensures the pro- duction of the different types of hemoglobin, from embryonic to fetal and adult, required at the different developmental stages. In humans, the switch from γ- to β- globin expression, resulting in the change from fetal hemoglobin (HbF) to adult hemoglobin (HbA) production, is the subject of intense investigation. In fact, the maintenance of expression of the fetal γ-globin gene in the adult can compensate for defects in β-globin synthesis causing β-hemoglobinopathies, the most common monogenic inherited human diseases.1-5 This evidence has focused the research on discovering γ-globin repressors in adult cells, several of which have been identified to-date, the best example being the transcriptional repressor Bcl11a-XL.6 By con- trast, less is known about possible specific activators of embryonic/fetal genes in early developmental stages.
Early murine erythropoiesis is sustained by two waves of cells of yolk sac origin. The first wave generates “primitive” red blood cells (EryP), which synthesize embryonic eY and βH1-globins; the second wave produces erythro-myeloid pro- genitors (EMP), which colonize the fetal liver and differentiate into erythroid and
Correspondence:
ANTONELLA ELLENA RONCHI1
antonella.ronchi@unimib.it
Received: October 30, 2019. Accepted: February 20, 2020. Pre-published: February 27, 2020.
https://doi.org/10.3324/haematol.2019.241224
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