Increased production of fetal hemoglobin (HbF) can ameliorate the severity of sickle cell disease and β-thalassemia 1. BCL11A represses the genes encoding HbF and regulates human hemoglobin switching through variation in its expression during development 2-7. However, the mechanisms underlying the developmental expression of BCL11A remain mysterious. Here we show that BCL11A is regulated at the level of mRNA translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a reciprocal pattern to BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, we show that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independent of its role in regulating let-7 microRNAs, and BCL11A is the major target of LIN28B-mediated HbF induction. Our results reveal a previously unappreciated mechanism underlying human hemoglobin switching that illuminates new therapeutic opportunities. The developmental switch from fetal to adult hemoglobin in humans has been extensively studied and is of substantial interest for developing approaches to induce fetal hemoglobin (HbF) to treat sickle cell disease and β-thalassemia 1,8. Through functional and genetic follow up of genome-wide association studies for HbF levels 9,10 , BCL11A has been identified as a key regulator of both developmental hemoglobin switching and silencing of HbF in the adult 1-7. BCL11A protein levels are developmentally regulated in humans such that, at the earlier developmental stages when HbF is highly expressed in erythroid cells, there is little or no BCL11A protein 2,3. In contrast, BCL11A protein is robustly expressed in adult erythroid cells that have low levels of HbF expression. Despite extensive studies, the basis of this developmental regulation of BCL11A protein expression and thereby the upstream regulators of human hemoglobin switching remain undefined. Consistent with earlier studies 2,3 , we found that BCL11A protein showed a gradient in expression across fetal, newborn, and adult erythroid cells at all stages of maturation (Fig. 1a and Extended Data Fig. 1a,b,d,h,i). Surprisingly, there was no substantial change in BCL11A mRNA expression between fetal, newborn, or adult erythroid cells (Fig. 1b and Extended Data Fig. 1c,e-g), suggesting a post-transcriptional mechanism underlying the observed variation in protein expression. This difference in protein levels between the developmental stages could not be attributed to variation in the maturation state of cells or to differences in BCL11A mRNA splicing (Extended Data Fig. 2). One possible post-transcriptional mechanism underlying the observed variation in protein expression could involve BCL11A protein being more readily degraded at the earlier developmental stages, as compared with adult erythroid cells. Since newborn...
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