BCL11A haploinsufficiency
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB31728 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3224620_1.fastq.gz | Fastqsanger.gz | |||
| ERR3224620_2.fastq.gz | Fastqsanger.gz | |||
| ERR3224621_1.fastq.gz | Fastqsanger.gz | |||
| ERR3224621_2.fastq.gz | Fastqsanger.gz | |||
| ERR3224622_1.fastq.gz | Fastqsanger.gz |
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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:Genetic depletion of the transcriptional repressor BCL11A in red blood cell precursors alleviates b-hemoglobinopathies by inducing the fetal g-globin genes. However, several additional erythroid genes are regulated by BCL11A and the effects of its deficiency on erythropoiesis are insufficiently described. We discovered that Cas9 disruption of the BCL11A intron 2 erythroid enhancer in CD34+ hematopoietic stem and progenitor cells (HSPCs) according to a clinically approved strategy caused impaired expansion and increased apoptosis of erythroid precursors in vitro and in vivo. Mutant colony-forming unit erythroid (CFU-e), proerythroblasts, and basophilic erythroblasts exhibited dysregulation of 94 genes (> 2-fold change, FDR < 0.05). 25 of which are likely direct targets of BCL11A. Differentially expressed genes were associated with numerous biological pathways that impact cell expansion and survival. Our findings show that BCL11A regulates additional aspects of erythropoiesis beyond g-globin gene repression.
2024-12-09 | GSE283794 | GEO
Project description:Genetic depletion of the transcriptional repressor BCL11A in red blood cell precursors alleviates b-hemoglobinopathies by inducing the fetal g-globin genes. However, several additional erythroid genes are regulated by BCL11A and the effects of its deficiency on erythropoiesis are insufficiently described. We discovered that Cas9 disruption of the BCL11A intron 2 erythroid enhancer in CD34+ hematopoietic stem and progenitor cells (HSPCs) according to a clinically approved strategy caused impaired expansion and increased apoptosis of erythroid precursors in vitro and in vivo. Mutant colony-forming unit erythroid (CFU-e), proerythroblasts, and basophilic erythroblasts exhibited dysregulation of 94 genes (> 2-fold change, FDR < 0.05). 25 of which are likely direct targets of BCL11A. Differentially expressed genes were associated with numerous biological pathways that impact cell expansion and survival. Our findings show that BCL11A regulates additional aspects of erythropoiesis beyond g-globin gene repression.
2024-12-09 | GSE283793 | GEO
Project description:BCL11A is a critical mediator of hemoglobin switching and gamma-globin silencing. In this study, we showed the BCL11A is required in vivo for developmental silencing of gamma-globin genes in adult animals. We used microarray to determine the changes in gene expression profile after loss of BCL11A in adult erythroid cells CD71+Ter119+ erythroid progenitor cells were FACS-sorted from bone marrows of 6-week old control (Bcl11a +/+) and BCL11A knockout (Bcl11a fl/fl EpoR-Cre+) mice.
2012-03-22 | E-GEOD-28333 | 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. 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:Prior evidence indicates that the erythroid cellular response to glucocorticoids (GC) has developmental specificity, namely, that developmentally more advanced cells that are undergoing or have undergone fetal to adult globin switching are more responsive to GC-induced expansion. To investigate the molecular underpinnings of this, we focused on the major developmental globin regulator BCL11A. We compared: a) levels of expression and nuclear content of BCL11A in adult erythroid cells upon GC stimulation; b) response to GC of CD34+ cells from patients with BCL11A microdeletions and reduced BCL11A expression, and; c) response to GC of two cellular models (HUDEP-2 and adult CD34+ cells) before and after reduction of BCL11A expression by shRNA. We observed that: a) GC-expanded erythroid cells from a large cohort of blood donors displayed amplified expression and nuclear accumulation of BCL11A; b) CD34+ cells from BCL11A microdeletion patients generated fewer erythroid cells when cultured with GC compared to their parents, while the erythroid expansion of the patients was similar to that of their parents in cultures without GC, and; c) adult CD34+ cells and HUDEP-2 cells with shRNA-depleted expression of BCL11A exhibit reduced expansion in response to GC. In addition, RNA-seq profiling of shRNA-BCL11A CD34+ cells cultured with and without GC was similar (very few differentially expressed genes), while GC-specific responses (differential expression of GILZ and of numerous additional genes) were observed only in controls cells with unperturbed BCL11A expression. These data indicate that BCL11A is an important participant of certain aspects of the stress pathway sustained by GC.
2024-09-01 | GSE274928 | GEO
Project description:Genetic depletion of the transcriptional repressor BCL11A in red blood cell precursors alleviates b-hemoglobinopathies by inducing the fetal g-globin genes. However, several additional erythroid genes are regulated by BCL11A and the effects of its deficiency on erythropoiesis are insufficiently described. We discovered that Cas9 disruption of the BCL11A intron 2 erythroid enhancer in CD34+ hematopoietic stem and progenitor cells (HSPCs) according to a clinically approved strategy caused impaired expansion and increased apoptosis of erythroid precursors in vitro and in vivo. Mutant colony-forming unit erythroid (CFU-e), proerythroblasts, and basophilic erythroblasts exhibited dysregulation of 94 genes (> 2-fold change, FDR < 0.05). 25 of which are likely direct targets of BCL11A. Differentially expressed genes were associated with numerous biological pathways that impact cell expansion and survival. Our findings show that BCL11A regulates additional aspects of erythropoiesis beyond g-globin gene repression.
2024-12-09 | GSE283796 | GEO
Project description:Genetic depletion of the transcriptional repressor BCL11A in red blood cell precursors alleviates b-hemoglobinopathies by inducing the fetal g-globin genes. However, several additional erythroid genes are regulated by BCL11A and the effects of its deficiency on erythropoiesis are insufficiently described. We discovered that Cas9 disruption of the BCL11A intron 2 erythroid enhancer in CD34+ hematopoietic stem and progenitor cells (HSPCs) according to a clinically approved strategy caused impaired expansion and increased apoptosis of erythroid precursors in vitro and in vivo. Mutant colony-forming unit erythroid (CFU-e), proerythroblasts, and basophilic erythroblasts exhibited dysregulation of 94 genes (> 2-fold change, FDR < 0.05). 25 of which are likely direct targets of BCL11A. Differentially expressed genes were associated with numerous biological pathways that impact cell expansion and survival. Our findings show that BCL11A regulates additional aspects of erythropoiesis beyond g-globin gene repression.
2024-12-09 | GSE283795 | GEO
Project description:Reactivation of fetal hemoglobin expression by down-regulation of BCL11A is a promising treatment of -hemoglobinopathies. A detailed understanding of BCL11A-mediated repression of -globin gene (HBG1/2) transcription is lacking, as studies to date used perturbations by shRNA or CRISPR/Cas9 gene editing. We leveraged the dTAG PROTAC platform to acutely deplete BCL11A protein in erythroid cells and examined consequences by PRO-seq, proteomics, chromatin accessibility, and histone profiling. Among ≤ 31 genes repressed by BCL11A, HBG1/2 and HBZ show the most abundant and progressive changes in transcription and chromatin accessibility upon BCL11A loss. Transcriptional changes at HBG1/2 were detected in < 2h. Robust HBG1/2 reactivation upon acute BCL11A-depletion occurred without loss of promoter 5methylcytosine (5mC). Using targeted protein degradation, we establish a hierarchy of gene reactivation at BCL11A targets, in which nascent transcription is followed by increased chromatin accessibility, and both are uncoupled from promoter DNA methylation at the HBG1/2 loci.
2023-10-24 | PXD030307 | Pride
Project description:Reactivation of fetal hemoglobin expression by down-regulation of BCL11A is a promising treatment of -hemoglobinopathies. A detailed understanding of BCL11A-mediated repression of -globin gene (HBG1/2) transcription is lacking, as studies to date used perturbations by shRNA or CRISPR/Cas9 gene editing. We leveraged the dTAG PROTAC platform to acutely deplete BCL11A protein in erythroid cells and examined consequences by PRO-seq, proteomics, chromatin accessibility, and histone profiling. Among ≤ 31 genes repressed by BCL11A, HBG1/2 and HBZ show the most abundant and progressive changes in transcription and chromatin accessibility upon BCL11A loss. Transcriptional changes at HBG1/2 were detected in < 2h. Robust HBG1/2 reactivation upon acute BCL11A-depletion occurred without loss of promoter 5methylcytosine (5mC). Using targeted protein degradation, we establish a hierarchy of gene reactivation at BCL11A targets, in which nascent transcription is followed by increased chromatin accessibility, and both are uncoupled from promoter DNA methylation at the HBG1/2 loci
2022-07-27 | PXD030301 | Pride