| Abstract |
The switch from fetal to adult hemoglobin is tightly regulated during erythropoiesis, and its dysregulation can contribute to β-hemoglobinopathies. Although transcriptional repression of γ-globin by BCL11A is well established, the posttranscriptional mechanisms that sustain BCL11A expression in adult erythroid cells remain incompletely understood. Here, we report that the long noncoding RNA UCA1/miR-148b-mediated regulatory axis is critical for globin gene switching. We identified miR-148b as a direct posttranscriptional regulator of BCL11A. lncRNA UCA1, which is abundantly expressed in adult erythroid cells, functions as a molecular decoy for miR-148b, thereby attenuating miR-148b-mediated repression of BCL11A. Depletion of UCA1 increases miR-148b availability and reduces BCL11A expression, which can lead to robust induction of γ-globin. Conversely, the ectopic expression of UCA1 restores BCL11A levels by antagonizing miR-148b, thereby promoting γ-globin silencing in adult erythroid cells. Mechanistically, UCA1 orchestrates a posttranscriptional regulatory axis that reinforces γ-globin silencing by stabilizing BCL11A levels in adult erythroid cells. Taken together, our studies uncover a previously unrecognized lncRNA-mediated mechanism that integrates miRNA activity with transcriptional control to fine-tune hemoglobin switching during adult erythropoiesis.
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