Regulation of BCL11A DNA binding and expression in human erythrocyte precursor HUDEP-2 cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE316022 | GEO | 2026/04/14
REPOSITORIES: GEO
Similar Datasets
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. Expression clone label: FBB (4 different subclones, with 2 arrays each), Control label: MelBirA Experiment Overall Design: Microarray expression analysis from parental control mouse erythroleukemia (MEL) cells containing the BirA enzyme (MelBirA cells) and cells containing tagged versions (FLAG-Biotag) of BCL11A. Two control datasets and eight datasets from four subclones containing tagged BCL11A are included.
2009-01-13 | E-GEOD-13283 | biostudies-arrayexpress
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. BCL11A siRNA label: B, NT siRNA label: N Experiment Overall Design: Microarray expression analysis from CD34-derived erythroid progenitors treated with either non-targeting (NT) control siRNAs or BCL11A targeting siRNAs. Six samples from the NT control and six samples from the BCL11A siRNA treatment are included. Cells were harvested on day 7 of erythroid differentiation after introduction of siRNAs on day 0 of the differentiation protocol. Experiment Overall Design: 6 BCL11A siRNA datasets, 6 control (NT) datasets
2009-01-13 | E-GEOD-13284 | biostudies-arrayexpress
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. BCL11A siRNA label: B, NT siRNA label: N Keywords: cell type comparsion
2008-12-05 | GSE13284 | GEO
Project description:Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the beta-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here we examine BCL11A as a potential regulator of HbF expression. The high HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the beta-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders. Expression clone label: FBB (4 different subclones, with 2 arrays each), Control label: MelBirA Keywords: cell type comparsion
2008-12-05 | GSE13283 | GEO
Project description:Hemoglobinopathies, such as sickle cell disease and β-thalassemia, are common genetic disorders remaining significant global health challenges due to their associated morbidity and mortality. Increasing fetal hemoglobin (HbF) levels has emerged as a promising therapeutic strategy for these disorders. In this study, we report MAZ as a repressor of γ-globin expression in human erythroid cells. Depletion of MAZ in HUDEP-2 and patient-derived β-thalassemia cells leads to significant inductions both of γ-globin mRNA and protein levels, resulting in increased HbF percentages and HbF+ erythroid cells. We demonstrate that MAZ occupies at the MYB promoter. MAZ depletion reduced MYB and BCL11A levels. Restoration of MYB re-silenced the γ-globin levels in MAZ depleted cells. Our findings uncover the MAZ-MYB axis in γ-globin regulation, highlighting MAZ as a potential target to enhance HbF levels in patients with hemoglobin disorders.
2025-11-01 | GSE281501 | GEO
Project description:Increasing fetal-type hemoglobin (HbF) expression in adult erythroid cells holds promise in the treatment of sickle cell disease (SCD) and -thalassemia. We have identified MLL1 complex as a critical regulator of fetal and embryonic hemoglobin repression. Knockdowns of MEN1 and KMT2A, encoding essential components of the complex, caused a significant downregulation of BCL11A expression and a substantial increase in - and -globin mRNA levels in HUDEP-2 cells. Significant binding of MEN1 and KMT2A were readily detected at the promoter and a critical enhancer of BCL11A in HUDEP-2 cells, suggesting that BCL11A is a direct transcriptional target of MLL1 complex. Consistent with these results, MEN1 or KMT2A knockdown in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation also significantly decreased their BCL11A expression and increased their - and -globin expression and the production of F cells in the culture. Treatment of these cells with MENIN inhibitors yielded similar results and promoted erythroid differentiation with minimal effects on their growth. These findings underscore a critical role of MLL1 complex in regulating fetal and embryonic hemoglobin expression and suggest that MENIN inhibitors could offer a promising therapeutic approach for sickle cell disease and -thalassemia.
2025-12-10 | GSE292144 | GEO
Project description:Hemoglobinopathies, including sickle cell disease and _-thalassemia, are global public health concerns. Induction of fetal-type hemoglobin (HbF) is a promising means to treat these disorders; however, precisely how HbF expression is silenced in adult erythroid cells is not fully understood. Here, we show that the LRF/ZBTB7A transcription factor is a potent repressor of HbF production. LRF inactivation derepresses embryonic/fetal _-globin expression in mouse and human adult erythroid cells. We employed genome-wide analysis of the transcriptome, chromatin accessibility and LRF occupancy sites, and demonstrate that LRF occupies the _-globin loci and maintains nucleosome density necessary for _-globin silencing. LRF confers its repressive activity through a unique NuRD repressor complex independent of BCL11A. Strikingly, human erythroid lines lacking both LRF and BCL11A exhibited almost a complete switch in expression from adult- to fetal-type globin, suggesting that these two factors cumulatively represent the near entirety of _-globin repressive activity in adult erythroid cells. RNA-seq, LRF ChIP-seq and ATAC-seq assays were used to investigtae LRF binding, effect of LRF depletion on transcription and chromatin landscape in mouse and human cells.
2016-01-15 | E-GEOD-74977 | biostudies-arrayexpress
Project description:Hemoglobinopathies, including sickle cell disease and _-thalassemia, are global public health concerns. Induction of fetal-type hemoglobin (HbF) is a promising means to treat these disorders; however, precisely how HbF expression is silenced in adult erythroid cells is not fully understood. Here, we show that the LRF/ZBTB7A transcription factor is a potent repressor of HbF production. LRF inactivation derepresses embryonic/fetal _-globin expression in mouse and human adult erythroid cells. We employed genome-wide analysis of the transcriptome, chromatin accessibility and LRF occupancy sites, and demonstrate that LRF occupies the _-globin loci and maintains nucleosome density necessary for _-globin silencing. LRF confers its repressive activity through a unique NuRD repressor complex independent of BCL11A. Strikingly, human erythroid lines lacking both LRF and BCL11A exhibited almost a complete switch in expression from adult- to fetal-type globin, suggesting that these two factors cumulatively represent the near entirety of _-globin repressive activity in adult erythroid cells.
2016-01-15 | GSE74977 | GEO
Project description:CRISPR editing of an intronic enhancer within the BCL11A gene reactivates fetal hemoglobin (HbF) in adult erythroid cells, serving as a gene-based therapy for hemoglobinopathies. However, the mechanisms underlying the remarkable efficacy of CRISPR-mediated enhancer ablation remain poorly understood. Ehancer RNAs transcribes from enhancer play a role in gene regulation. Here, we apply PRO-seq in wild-type and sg1617-edited HUDEP-2 cells to determine the effects of sg1617 editing on enhancer RNA transcription.
2025-11-13 | GSE292697 | GEO
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.
2019-10-09 | MSV000084443 | MassIVE