Ontology highlight
ABSTRACT:
PROVIDER: PRJNA558438 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10350700_1.fastq.gz | Fastqsanger.gz | |||
| SRR10350700_2.fastq.gz | Fastqsanger.gz | |||
| SRR10350701_1.fastq.gz | Fastqsanger.gz | |||
| SRR10350701_2.fastq.gz | Fastqsanger.gz | |||
| SRR10350702_1.fastq.gz | Fastqsanger.gz |
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Project description:Beta-hemoglobinopathies caused by mutations in adult-expressed HBB can be treated by re-activating the adjacent paralogous genes HBG1 and HBG2 (HBG), which are normally silenced perinatally. Although HBG expression is induced by global demethylating drugs, their mechanism is poorly understood and toxicity limits their use. We identified the DNMT1-associated maintenance methylation protein UHRF1 as a mediator of HBG repression in a genome-wide screen. Loss of UHRF1 in the adult-type erythroid cell line HUDEP2 caused global demethylation and HBG activation that was reversed upon localized promoter re-methylation. Conversely, targeted demethylation of the HBG promoters activated their genes in HUDEP2 or primary CD34+ cell-derived erythroblasts. Mutation of MBD2, a CpG-methylation reading component of the NuRD complex, to impair methylation sensitivity recapitulated the effects of promoter demethylation. Our studies demonstrate that localized CpG-methylation at the HBG promoters facilitates developmental silencing and identify a targeted therapeutic approach for b-hemoglobinopathies via epigenomic editing.
2025-06-24 | GSE284291 | GEO
Project description:Beta-hemoglobinopathies caused by mutations in adult-expressed HBB can be treated by re-activating the adjacent paralogous genes HBG1 and HBG2 (HBG), which are normally silenced perinatally. Although HBG expression is induced by global demethylating drugs, their mechanism is poorly understood and toxicity limits their use. We identified the DNMT1-associated maintenance methylation protein UHRF1 as a mediator of HBG repression in a genome-wide screen. Loss of UHRF1 in the adult-type erythroid cell line HUDEP2 caused global demethylation and HBG activation that was reversed upon localized promoter re-methylation. Conversely, targeted demethylation of the HBG promoters activated their genes in HUDEP2 or primary CD34+ cell-derived erythroblasts. Mutation of MBD2, a CpG-methylation reading component of the NuRD complex, to impair methylation sensitivity recapitulated the effects of promoter demethylation. Our studies demonstrate that localized CpG-methylation at the HBG promoters facilitates developmental silencing and identify a targeted therapeutic approach for b-hemoglobinopathies via epigenomic editing.
2025-06-24 | GSE284290 | GEO
Project description:Beta-hemoglobinopathies caused by mutations in adult-expressed HBB can be treated by re-activating the adjacent paralogous genes HBG1 and HBG2 (HBG), which are normally silenced perinatally. Although HBG expression is induced by global demethylating drugs, their mechanism is poorly understood and toxicity limits their use. We identified the DNMT1-associated maintenance methylation protein UHRF1 as a mediator of HBG repression in a genome-wide screen. Loss of UHRF1 in the adult-type erythroid cell line HUDEP2 caused global demethylation and HBG activation that was reversed upon localized promoter re-methylation. Conversely, targeted demethylation of the HBG promoters activated their genes in HUDEP2 or primary CD34+ cell-derived erythroblasts. Mutation of MBD2, a CpG-methylation reading component of the NuRD complex, to impair methylation sensitivity recapitulated the effects of promoter demethylation. Our studies demonstrate that localized CpG-methylation at the HBG promoters facilitates developmental silencing and identify a targeted therapeutic approach for b-hemoglobinopathies via epigenomic editing.
2025-06-24 | GSE284289 | GEO
Project description:Sickle cell disease (SCD) is a severe genetic disease caused by a mutation affecting the production of the β-globin chain. Its clinical severity is mitigated by the co-inheritance of mutations that reactivate the production of fetal hemoglobin (HbF) in adults. Here, we investigated the epigenetic regulation of the HBG genes and developed a novel approach based on programmable epigenome editing. Analysis of epigenetic marks at the HBG promoters revealed a distinct pattern of modifications in adult versus fetal erythroid cells. Our studies showed efficient HBG reactivation in the HEK293T cell line and in the progeny of hematopoietic stem and progenitor cells (HSPCs) when using activating epigenome editors targeting the HBG promoters, reaching up to 50% of HbF production and a substantial correction of the sickling phenotype. Our findings highlight the pivotal role of epigenetic modifications in the regulation of the β-globin locus and demonstrate that epigenome reprogramming represents a promising alternative to DNA-cleaving enzymes. This approach mitigates the risks associated with genotoxicity, providing a safe and effective strategy for treating SCD.
2025-05-15 | GSE283100 | GEO
Project description:Transcriptional enhancers can be in physical proximity with their target genes via chromatin looping. The enhancer at the beta-globin locus (LCR) contacts the fetal (HBG) and adult (HBB) type beta-globin genes during corresponding developmental stages. We previously demonstrated that forcing proximity between the LCR and HBG genes in cultured adult-stage erythroid cells can activate HBG transcription. Activation of HBG expression in erythroid cells is of benefit to patients with sickle cell disease. Here, using the beta-globin locus as a model we provide proof-of-concept at the organismal level that forced enhancer re-wiring might present a strategy to alter gene expression for therapeutic purposes. Hematopoietic stem and progenitor cells (HSPC) from mice bearing human beta-globin genes were transduced with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) that fosters LCR-HBG contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated HBG expression. Vectors containing ZF-Ldb1 were optimized for activity in cultured human and rhesus erythroid cells. Upon transplantation into rhesus macaques, erythroid cells from HSPCs expressing ZF-Ldb1 displayed elevated HBG production. These findings in two animal models suggest that forced redirection of gene regulatory elements may be used to alter gene expression to treat disease.
2023-02-08 | GSE221182 | GEO
Project description:Human genetics has validated de-repression of fetal gamma globin (HBG) in adult erythroblasts as a powerful therapeutic paradigm in diseases involving defective adult beta globin (HBB)1. To identify novel factors involved in the switch from HBG to HBB expression, we performed Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq)2 on discrete sorted erythroblast populations derived from bone marrow (BM) or cord blood (CB) progenitors, representing adult and fetal states, respectively. Comparison of the ATAC-seq profiles revealed enrichment of NFI DNA binding motifs and increased chromatin accessibility at the NFIX promoter in BM populations relative to CB populations, suggesting that NFIX may repress HBG. NFIX knockdown in BM cells increased HBG mRNA and fetal hemoglobin (HbF) protein levels, coincident with increased chromatin accessibility and decreased DNA methylation at the HBG promoter. Conversely, overexpression of NFIX in CB cells reduced HbF levels. Identification of NFIX as a novel target for HbF activation has potential implications in the development of therapeutics for hemoglobinopathies.
2023-05-31 | GSE196731 | GEO
Project description:Removal of promoter DNA methylation by epigenome editing reverses HBG silencing [RNA-seq]
| PRJNA1198349 | ENA
Project description:Removal of promoter DNA methylation by epigenome editing reverses HBG silencing [CUT&RUN]
| PRJNA1198350 | ENA
Project description:Removal of promoter DNA methylation by epigenome editing reverses HBG silencing [ATAC-seq]
| PRJNA1198351 | ENA