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A significant change in the 5-hmCSeal signal is observed between UT-7 WT cells and cells carrying single or dual phospho-site substitution cells around the BCL11A gene enhancer region

ABSTRACT: An allogeneic blood stem cell transplantation is the only durable cure for sickle cell disease. Non-cell therapy approaches that target suppressor proteins of fetal hemoglobin gene (HBG) expression will provide the basis for novel therapies. Here we identify TET2 dioxygenase as a unifying regulator of both HBG suppressor BCL11A, and HBG activators HBBP1 and BGLT3 lncRNAs. Down regulation of TET2 functions by replacement of a single c-terminus phospho tyrosine residue is sufficient for activation of HBG by a mechanism that involves loss of TET2 binding with transcription factor GATA1 and redistribution of DNA hydroxymethylation in BCL11A enhancer and HBBP1/BGLT3 genes. By creating a transgenic sickle cell mouse in a Tet2 phospho tyrosine null background we demonstrate reactivation of fetal hemoglobin with resulting improvement in anemia and loss in sickle cell morphology and normalization of blood counts thereby identifying a mechanism for HBG activation without the need for gene editing approach.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319295 | GEO | 2026/02/18

REPOSITORIES: GEO

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Project description:Basak A, Munschauer M, Lareau CA, Montbleau KE, Ulirsch JC, Hartigan CR, Schenone M, Lian J, Wang Y, Huang Y, Wu X, Gehrke L, Rice CM, An X, Christou HA, Mohandas N, Carr SA, Orkin SH, Chen JJ, Lander ES, and Sankaran VG. Increased production of the beta-like gamma-globin genes that form fetal hemoglobin can ameliorate the severity of sickle cell disease and beta-thalassemia, the major hemoglobin disorders. BCL11A is a key repressor of the gamma-globin genes and is expressed in a developmental stage-specific manner to regulate the physiologic fetal-to-adult hemoglobin switch. Despite extensive studies, the upstream mechanisms underlying the developmental expression of BCL11A and hemoglobin switching in humans have remained mysterious. Here we show that BCL11A is regulated at the level of mRNA translation during human hematopoietic development. While BCL11A mRNA is comparably expressed at all developmental stages in erythroid cells, robust protein expression only occurs in adult erythroid cells. Importantly, at the earlier stages of development, the observed reduction in protein expression is attributable to decreased synthesis and not increased degradation of BCL11A. While BCL11A protein is not well synthesized at these earlier stages of development, its mRNA curiously continues to be associated with ribosomes. Through unbiased proteomic analyses in erythroid cells, we demonstrate that the RNA-binding protein LIN28B, which is developmentally expressed in a reciprocal pattern to BCL11A, directly interacts with ribosomes. We show that the observed suppression of BCL11A protein translation is mediated by LIN28B through a direct interaction with BCL11A mRNA and independent of its role in let-7 microRNA biogenesis. Finally, we show that BCL11A is the major functional target in LIN28B-mediated fetal hemoglobin induction. Our results reveal a previously unappreciated regulatory mechanism underlying human hemoglobin switching and illuminate opportunities for developing improved treatments for sickle cell disease and beta-thalassemia.

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A significant change in the 5-hmCSeal signal is observed between UT-7 WT cells and cells carrying single or dual phospho-site substitution cells around the BCL11A gene enhancer region

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