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-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.