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Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia [ChIP-seq]

ABSTRACT: The fetal-to-adult hemoglobin switch is regulated in a developmental stage-specific manner and reactivation of fetal hemoglobin (HbF) has therapeutic potential for β-hemoglobinopathies. Although BCL11A and ZBTB7A interact with their coregulators, reportedly mediating most γ-globin transcriptional silencing in erythroid in trans, and in cis, the molecular mechanism underlying the epigenetic dysregulation of the switch remains largely unclear. Here we showed that epigenetic inactivation of an ETS2 repressor factor (ERF) reactivates γ-globin expression during stress erythropoiesis, and ERF depletion elevates γ-globin in erythroid cells and in erythroid progenies from the edited HSPCs engrafted into immunodeficient mice. ERF represses γ-globin by directly binding to two motifs regulating HBG expression, independently of the major HbF repressors BCL11A and ZBTB7A. We further uncovered that an lncRNA, RP11-196G18.23 mediates ERF promoter hypermethylation resulting in reactivation of g-globin. Herein, the epigenetic alterations were identified as novel modulators ameliorating the severity of b-thalassemia, thus providing novel therapeutic targets for β-hemoglobinopathies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE160602 | GEO | 2020/12/27

REPOSITORIES: GEO

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Epigenetic inactivation of ERF reactivates γ-globin expression in β-thalassemia [RNA-seq]

Project description:The fetal-to-adult hemoglobin switch is regulated in a developmental stage-specific manner and reactivation of fetal hemoglobin (HbF) has therapeutic potential for β-hemoglobinopathies. Although BCL11A and ZBTB7A interact with their coregulators, reportedly mediating most γ-globin transcriptional silencing in erythroid in trans, and in cis, the molecular mechanism underlying the epigenetic dysregulation of the switch remains largely unclear. Here we showed that epigenetic inactivation of an ETS2 repressor factor (ERF) reactivates γ-globin expression during stress erythropoiesis, and ERF depletion elevates γ-globin in erythroid cells and in erythroid progenies from the edited HSPCs engrafted into immunodeficient mice. ERF represses γ-globin by directly binding to two motifs regulating HBG expression, independently of the major HbF repressors BCL11A and ZBTB7A. We further uncovered that an lncRNA, RP11-196G18.23 mediates ERF promoter hypermethylation resulting in reactivation of g-globin. Herein, the epigenetic alterations were identified as novel modulators ameliorating the severity of b-thalassemia, thus providing novel therapeutic targets for β-hemoglobinopathies.

2020-12-27 | GSE160601 | GEO

KLF1 directly activates expression of the novel fetal globin repressor, ZBTB7A/LRF, in erythroid cells

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

The LRF/ZBTB7A transcription factor is a BCL11A-independent repressor of fetal hemoglobin

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

RNAi profiling by array of human CD34-derived erythroid progenitors treated with BCL11A siRNAs

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

The LRF/ZBTB7A transcription factor is a BCL11A-independent repressor of fetal hemoglobin

2016-01-15 | GSE74977 | GEO

Transcription profiling of mouse erythroleukemia (MEL) cells expressing tagged versions of BCL11A

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

Human CD34-derived erythroid progenitors treated with BCL11A siRNAs

2008-12-05 | GSE13284 | GEO

Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch

Project description:Fetal hemoglobin (HbF) level is genetically controlled and modifies severity of adult hemoglobin (HbA) disorders. Common genetic variation affects expression of BCL11A, a critical regulator of HbF silencing. Current models suggest that BCL11A acts at a distance from the gamma-globin genes via long-distance chromosomal interactions. Here we use a functional cellular assay and protein-binding microarray to establish a requirement for a zinc-finger cluster of BCL11A for globin repression, and identify a preferred DNA recognition sequence (TGACCA). The motif is present in embryonic and fetal-expressed globin promoters, and duplicated in gamma-globin promoters, yet only the distal motif is mutated in alleles of individuals with hereditary persistence of hemoglobin. Using CUT&RUN to map protein binding sites, we detected BCL11A occupancy preferentially at the distal motif, and validated its absence in HbF-expressing, promoter-edited erythroid cells. Taken together, our findings reveal that direct gamma-globin gene promoter repression by BCL11A underlies hemoglobin switching.

2018-03-30 | GSE104676 | GEO

Mouse Erythroleukemia (MEL) Cells Expressing Tagged Versions of BCL11A

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

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells

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

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