UCA1 lncRNA represses γ-globin expression by sequestering miR-148b, a key post-transcriptional regulator of BCL11A

Fetal hemoglobin (HbF; α₂γ₂) reactivation is a promising strategy to ameliorate β-hemoglobinopathies. However, limited understanding of γ-globin (HBG1/2) regulation constrains development of therapeutic interventions. BCL11A, a key transcriptional repressor of γ-globin, is central to HbF silencing during adult erythropoiesis. Here, we identify a new post-transcriptional regulatory mechanism involving the lncRNA-UCA1 and miR-148b that modulates BCL11A expression. Using UCA1 knockdown and overexpression strategies, combined with in vivo crosslinking and transcriptomic analyses, we demonstrate that UCA1 functions as a competing endogenous RNA (ceRNA), sequestering miR-148b and thereby attenuating its repressive effect on BCL11A. In the present study, we have elucidated the physiological significance of this interaction in adult erythroid cells, including CD34⁺ HSPCs and HUDEP-2 cells, in which UCA1 depletion led to robust γ-globin induction, a phenotype recapitulated by miR-148b overexpression. These findings uncover a previously unrecognized lncRNA-miRNA-mRNA regulatory axis and highlight the UCA1/miR-148b axis as a potential therapeutic target for HbF reactivation in β-hemoglobinopathies.