The LRF/ZBTB7A transcription factor is a BCL11A-independent repressor of fetal hemoglobin
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ABSTRACT:
PROVIDER: PRJNA302116 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2923110_1.fastq.gz | Fastqsanger.gz | |||
| SRR2923110_2.fastq.gz | Fastqsanger.gz | |||
| SRR2923120_1.fastq.gz | Fastqsanger.gz | |||
| SRR2923120_2.fastq.gz | Fastqsanger.gz | |||
| SRR2923130.fastq.gz | Fastqsanger.gz |
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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:Genes encoding the human β-like hemoglobin proteins undergo a developmental switch from fetal γ-globin to adult β-globin expression at around the time of birth. β-hemoglobinopathies, such as sickle cell disease and β-thalassemia, result from mutations affecting the adult β-globin gene. The only treatment options currently available carry significant side-effects. Analyses of heritable variations in fetal hemoglobin (HbF) levels have provided evidence that reactivation of the silenced fetal γ-globin genes in adult erythroid cells is a promising therapy. The γ-globin repressor BCL11A has become the major focus with several studies investigating its regulation and function as a first step to inhibiting its expression or activity. However, a second repression mechanism has recently been shown to be mediated by the transcription factor ZBTB7A/LRF, suggesting that understanding the regulation of ZBTB7A may also be useful. Here we show that KLF1 directly drives expression of ZBTB7A in erythroid cells by binding to its proximal promoter. We have also uncovered an erythroid-specific regulation mechanism, leading to the upregulation of a novel ZBTB7A transcript in the erythroid compartment. The demonstration that ZBTB7A, like BCL11A, is a KLF1 target gene also fits with the observation that reduced KLF1 expression or activity is associated with HbF derepression.
2017-04-13 | GSE97671 | GEO
Project description:B-hemoglobinopathies such as Sickle Cell Disease (SCD) and b-thalassemia result from mutations in the adult b-globin gene. Reactivating the developmentally silenced fetal g-globin gene is a therapeutic goal for treating SCD and b-thalassemia1. Some forms of Hereditary Persistence of Fetal Hemoglobin (HPFH), a rare benign condition in which individuals express g‑globin throughout adulthood, are caused by point mutations in the g‑globin gene promoter at regions residing ~115 and 200 base pairs upstream of the transcription start site. Here we show that the major fetal globin repressors BCL11A and ZBTB7A/LRF directly bind to the -115 and ‑200 sites, respectively. Furthermore, introduction of naturally occurring HPFH mutations into erythroid cells by CRISPR/Cas9 disrupts repressor binding and raises g‑globin expression. These findings resolve the mystery surrounding how these HPFH mutations operate and demonstrate that BCL11A and ZBTB7A/LRF are major direct repressors of the fetal globin gene.
2018-01-29 | GSE103445 | GEO
Project description:ChIP-seq for LRF/ZBTB7A in untransfected or LRF/ZBTB7A-overexpressing K562 cells, with or without hemin/EPO treatment and in K562 LRF/ZBTB7A-Knockdown cells
2022-07-13 | GSE200135 | 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
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216190 | GEO
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216194 | GEO
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216196 | GEO
Project description:The fetal hemoglobin (HBG) regulator BCL11A is repressed by HIC2 to regulate hemoglobin switching. HIC2 itself is under developmental control, highly expressed in fetal tissues and decreased in adult cells, but the mechanism of this developmental regulation is unclear. Here, we demonstrate that HIC2 is developmentally controlled by miRNAs, and loss of global miRNA biogenesis through DICER1 depletion leads to upregulation of HIC2 and HBG. We subsequently identify the adult-expressed let-7 miRNA family as a repressor of HIC2 expression. Ectopic expression of let-7 in fetal-type cells repressed HIC2 levels, while let-7 inhibition in adult erythroblasts upregulated HIC2 levels. Let-7 regulates BCL11A and HBG through induction of HIC2 and reduction of GATA1 binding at the BCL11A erythroid enhancer. Finally, HIC2 depletion rescues BCL11A-mediated repression of fetal hemoglobin in let-7 inhibited cells. Together these data demonstrate a key miRNA-mediated mechanism for developmental regulation of BCL11A expression and fetal hemoglobin repression in adult erythroid cells.
2024-02-05 | GSE216195 | GEO