In:
Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 106, No. 2 ( 2020-02-27), p. 474-482
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.
Type of Medium:
Online Resource
ISSN:
1592-8721
,
0390-6078
DOI:
10.3324/haematol.2019.241224
Language:
Unknown
Publisher:
Ferrata Storti Foundation (Haematologica)
Publication Date:
2020
detail.hit.zdb_id:
2186022-1
detail.hit.zdb_id:
2030158-3
detail.hit.zdb_id:
2805244-4
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