Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-cell transcriptomics reveals heterocellular g-globin gene expression in Agdb-thalassemia

ABSTRACT: To determine the heterogeneity of g-globin expression in the context of deletions that induce fetal hemoglobin, single-cell RNA-seq was performed on primary reticulocytes and undifferentiated HUDEP-2 cells. Single-cell RNA-sequencing (10x Genomics) showed participants and cell lines with the Agdb-thalassemia deletion had overall lower g-globin expression and maintained a lower %HBG expression (HBG/(HBG+HBB)) compared to participants and cell lines with deletional HPFH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280004 | GEO | 2026/02/25

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Project description:We have identified putative repressor region (PRR) to exon-1 of β-globin (βE1) in the β-globin cluster as a core region in alll the HPFH deletions that activates fetal hemoglobin and silences adult hemoglobin. Here we charactised the transcriptome of the erythroblasts derived from PRR-βE1 gene edited HSPCs. Transcriptome analysis showed an increased expression of HBG, HBBP1 and decreased expression of HBB transcripts compared to control.

2022-04-25 | GSE201346 | GEO

Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies [4C]

Project description:We have identified putative repressor region (PRR) to exon-1 of β-globin (βE1) in the β-globin cluster as a core region in alll the HPFH deletions that activates fetal hemoglobin and silences adult hemoglobin. To test the impact of PRR-βE1 gene editing in β-globin cluster configuration, we employed Circular chromosome conformation capture (4C) analysis to assess the LCR interaction to the gamma-globin promoter. Using HBG2 promoter as viewpoint,4C analysis showed an increased interaction of HBG promoter to the hypersensitive (HS) sites of the LCR in HUDEP-2 clones harbouring PRR-βE1 biallelic deletions compared to control HUDEP-2 cells. Link for 4C output files Mendeley - Venkatesan, Vigneshwaran (2022), “4C data set ”, Mendeley Data, V1, doi: 10.17632/cz3thnr9kf.1

2022-04-26 | GSE201388 | GEO

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

Project description: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.

2022-01-20 | GSE194064 | GEO

Ancestral beta-globin gene haplotypes modify beta-thalassemia severity in a mouse model [Ery]

Project description:beta-Thalassemia is a prevalent anemia caused by mutations in the HBB (beta-globin) gene. We show that the severity of beta-thalassemia in the frequently studied Hbb(th3/+) mouse model is influenced by ancestral beta-globin gene (Hbb) haplotypes that differ in common strains.

2024-12-18 | GSE260900 | GEO

Chromatin Accessibility Mapping of Primary Erythroid Cell Populations Leads to Identification and Validation of NFIX As a Novel Fetal Hemoglobin Repressor

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 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 sorted erythroid lineage cells derived from bone marrow (BM) or cord blood (CB), representing adult and fetal states, respectively. BM to CB cell ATAC-seq profile comparisons revealed genome-wide enrichment of NFI DNA binding motifs and increased NFIX promoter chromatin accessibility, 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 and validation of NFIX as a new target for HbF activation has implications in the development of therapeutics for hemoglobinopathies.

2023-06-07 | GSE234155 | GEO

Chromatin Accessibility Mapping of Primary Erythroid Cell Populations Leads to Identification and Validation of NFIX As a Novel Fetal Hemoglobin Repressor

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

Identification of novel HPFH-like mutations by CRISPR base editing that elevate the expression of fetal hemoglobin

Project description:CRISPR-Cas base editors are preferred tool for genome editing as they generate desired editing without any double strand break in the genome, as double stand break is detrimental to the cells. In our study we have demonstrated the significance of base editors in editing the highly homologous HBG promoter (HBG1 and HBG2) region to introduce novel HPFH-like mutation to elevate HbF for therapeutical applications. Previous studies revealed that the base editors can cause unintended Cas-independent edits at transcriptome level. To validate off-target at RNA level, we performed a transcriptome wide analysis. The frequency of unintended edits in the HUDEP-2 stable cell lines expressing the base editors with the gRNA were not significant compared to the control. We determined the ABE mediated A to I conversion and CBE mediated C to U conversion across the base edited samples. The RNA off-target analysis was carried out with the help of REDItools v 2 tool. This data suggests that despite high on-target editing in DNA, the Cas-independent RNA off-target were not at detectable range compared to control. The differential expression of 34 selected genes which necessitate globin regulation were compared between the unedited HUDEP WT, CBE control, ABE control, and edited ABE (with gRNA 2/11) and edited CBE (with gRNA 2/11). We observed that there is no significant differential gene expression between the edited and control cells except the gamma and delta globin genes. These results suggest that base editors are preferred tools to edit highly homologous HBG promoter region to created HPFH-like mutations inducing HbF levels without causing double strand breaks, larger deletions and no significant RNA off-targets which are detrimental to the gene edited cells.

2022-01-02 | GSE192801 | GEO

Ancestral β-globin gene haplotypes modify β-thalassemia severity in a mouse model [bone marrow, spleen]

Project description:β-Thalassemia is a prevalent anemia caused by mutations in the HBB (β-globin) gene. We show that the severity of β-thalassemia in the frequently studied Hbbth3/+ mouse model is influenced by ancestral β-globin gene (Hbb) haplotypes that differ in common strains.

2024-12-18 | GSE260901 | GEO

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

Forced enhancer-promoter rewiring to alter gene expression in animal models

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data