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Disrupting the adult-globin promoter alleviates promoter competition and reactivates foetal-globin gene expression

ABSTRACT: The benign condition Hereditary Persistence of Foetal Haemoglobin (HPFH) is known to ameliorate symptoms when co-inherited with beta-haemoglobinopathies, such as sickle cell disease and beta-thalassaemia. The condition is sometimes associated with point mutations in the foetal globin promoters that disrupt the binding of the repressors BCL11A or ZBTB7A/LRF, which have been extensively studied. HPFH is also associated with a range of deletions within the beta-globin locus that all reside downstream of the foetal HBG2 gene. These deletional forms of HPFH are poorly understood and are the focus of this study. Numerous different mechanisms have been proposed to explain how downstream deletions can boost the expression of the foetal globin genes, including the deletion of silencer elements, of genes encoding non-coding RNA, and bringing downstream enhancer elements into proximity with the foetal globin gene promoters. Here we systematically analyse the deletions associated with both HPFH and a related condition known as beta-thalassaemia and propose a unifying mechanism. In all cases where foetal globin is up-regulated, the proximal adult beta-globin (HBB) promoter is deleted. We use CRISPR gene editing to delete or disrupt elements within the promoter and find that virtually all mutations that reduce promoter activity, result in elevated foetal globin expression. These results fit with previous models where the foetal and adult globin genes compete for the distal Locus Control Region and suggest that targeting the promoter might be explored to elevate foetal globin and reduce sickle globin expression as a treatment for beta-haemoglobinopathies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE194064 | GEO | 2022/01/20

REPOSITORIES: GEO

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Natural regulatory mutations elevate fetal globin via disruption of BCL11A or ZBTB7A binding

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2018-01-29 | GSE103445 | GEO

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2022-02-16 | PXD024259 | Pride

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies

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2020-01-23 | PXD006889 | Pride

Activation of γ-globin gene expression by GATA1 and NF-Y in hereditary persistence of fetal hemoglobin

Project description:Naturally occurring mutations in the Î³-globin promoters can result in hereditary persistence of fetal hemoglobin (HPFH), a benign condition that ameliorates the severity of Î²-hemoglobinopathies through increased post-natal fetal hemoglobin (HbF) expression. Mutations in the Î³-globin promoters result in loss or de novo recruitment of transcription factors, yet the cis-regulatory elements involved in Î³-globin transcription in the context of HPFH are not clearly defined. We demonstrate that the -115 cluster of HPFH mutations require GATA1 binding to at -186 in cooperation with NF-Y at the proximal CCAAT box at -85 for Î³-globin expression. We show that multiple HPFH mutations increase HbF in an erythroid cell line and result in GATA1 binding at -186. Mutation of the -186 GATA motif in HPFH erythroid cell lines and erythroid-differentiated CD34+ cells resulted in loss of GATA1 binding and reduction in fetal hemoglobin. NF-Y ChIP-seq in HPFH erythroid cell lines demonstrated binding to the proximal CCAAT box at -85 was also found to be critical for HPFH-mediated Î³-globin expression. Together, the -186 GATA motif and -85 proximal CCAAT box function in an additive and independent manner. Our results reveal detailed evidence for common, positive acting cis-regulatory elements that may provide more general mechanisms for erythroid gene expression.

2021-04-22 | GSE152338 | GEO

Disrupting the adult-globin promoter alleviates promoter competition and reactivates foetal-globin gene expression

Project description:Disrupting the adult-globin promoter alleviates promoter competition and reactivates foetal-globin gene expression

| PRJNA798972 | ENA

Characterization of deletions of the HBB locus by array comparative genomic hybridization

Project description:Array-CGH used to characterize HBB deletions causing beta thalassemia and HPFH Two-color experiment comparing thalssemia/HPFH subjects with normal DNA

2015-05-06 | E-GEOD-68587 | biostudies-arrayexpress

Epigenetic modifications and chromosome conformations of the beta globin locus throughout development

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2015-01-26 | E-GEOD-35375 | biostudies-arrayexpress

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.

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