UCA1 lncRNA represses γ-globin expression by sequestering miR-148b, a key post-transcriptional regulator of BCL11A
Rahaman, M.; Bhattacharya, S.; Mukherjee, M.; Bhowmick, C.; Shukla, P. C.; Dolai, T. K.; Chakravorty, N.
Show abstract
Fetal hemoglobin (HbF; 2{gamma}2) reactivation is a promising strategy to ameliorate {beta}-hemoglobinopathies. However, limited understanding of {gamma}-globin (HBG1/2) regulation constrains development of therapeutic interventions. BCL11A, a key transcriptional repressor of {gamma}-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 {gamma}-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 {beta}-hemoglobinopathies.
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