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.
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Frigo C, Pastori V, Zambanini G, Fabiano M, Ahmed S, Citterio E, Cantù C, Ronchi AE
Haematologica 111 (5) 1747-1758 [2026-05-01; online 2025-11-27]
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 COUP-TFII 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 Lin28B, a known post-transcriptional 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.
PubMed 41307130
DOI 10.3324/haematol.2025.288485
Crossref 10.3324/haematol.2025.288485