COUP-TFII regulates hemoglobin switching by activating the BCL11A-XL repressor Lin28B and directly binding δ and β globin promoters in fetal versus adult erythroid cells

The reactivation of fetal globin genes is the most promising treatment for β-hemoglobinopathies. This implies the reversal of the naturally occurring hemoglobin switching. Here, we show that expression of the orphan nuclear receptor COUP-TFII in adult HUDEP2 erythroid precursor cells activates γ-glo...

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Vydáno v:	Haematologica (Roma) Ročník 999; číslo 1
Hlavní autoři:	Frigo, Carlotta, Pastori, Valentina, Zambanini, Gianluca, Fabiano, Martina, Ahmed, Sajeela, Citterio, Elisabetta, Cantù, Claudio, Ronchi, Antonella Ellena
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Italy Ferrata Storti Foundation 27.11.2025
ISSN:	1592-8721, 0390-6078, 1592-8721
On-line přístup:	Získat plný text
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Popis
Shrnutí:	The reactivation of fetal globin genes is the most promising treatment for β-hemoglobinopathies. This implies the reversal of the naturally occurring hemoglobin switching. Here, we show that expression of the orphan nuclear receptor COUP-TFII in adult HUDEP2 erythroid precursor cells activates γ-globin (HbF) at the expense of β-adult globin by specific occupation of the "adult" δ-β-region within the β-locus. Notably, although COUPT-FII and the main γ-globin repressor BCL11A-XL share a similar DNA binding consensus and a large number of chromatin targets, including the locus control region of the β-locus itself, they bind differentially to the γ and β promoters, eliciting an opposite transcriptional outcome. In addition, we find that COUP-TFII activates LinN28B, a known posttranscriptional repressor of BCL11A-XL. Our work identifies a molecular mechanism that could be leveraged to increase γ-globin levels in patients affected by β-hemoglobinopathies.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1592-8721 0390-6078 1592-8721
DOI:	10.3324/haematol.2025.288485