Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1193132 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31577939_1.fastq.gz | Fastqsanger.gz | |||
| SRR31577939_2.fastq.gz | Fastqsanger.gz | |||
| SRR31577940_1.fastq.gz | Fastqsanger.gz | |||
| SRR31577940_2.fastq.gz | Fastqsanger.gz | |||
| SRR31577941_1.fastq.gz | Fastqsanger.gz |
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Project description:Delta-Beta thalassemia is an unusual variant of thalassemia caused by large deletions in the β globin gene cluster involving δ- and β-globin genes. The mutations are characterized by high fetal hemoglobin with significant phenotypic diversity. Routinely used diagnostic tests targeting point mutations and small insertions, deletions of the β-globin gene are not suitable for detection of large deletion mutations. This is overcome by either direct globin chain synthesis analysis or beta-cluster gene analysis using different methods. In the current study, we use direct globin chain analysis to diagnose a family with δβ-thalassemia using high resolution mass spectrometry.
2024-08-09 | PXD044775 | Pride
Project description:Alpha thalassemia major (ATM) is an inherited blood disorder caused by the absence of all four α-globin genes (HBA2/1), resulting in severe anemia and lifelong transfusion dependence. While allogeneic hematopoietic stem cell transplant (HSCT) offers a potential cure, donor availability remains limited. We present a gene therapy approach for autologous HSCT, using lentiviral vectors (LVs) to deliver HBA2 under the regulation of optimized β-globin locus control region (LCR) enhancers, restoring α-globin expression. The best-performing LVs, EV-α and EV-α-UV, achieved 90-100% transduction efficiency in human hematopoietic stem and progenitor cells (HSPCs), optimal vector copy numbers, and a safe integration profile. ATM-derived HSPCs from three donors treated with these LVs yielded α/β-globin mRNA and chain ratios within the therapeutic range (~0.5+), and restored hemoglobin levels by 50 to 100%. These findings establish the safety and clinical potential of EV-α and EV-α-UV as a promising autologous stem cell gene therapy for ATM.
2025-07-10 | GSE292575 | GEO
Project description:Hemoglobinopathies are the most common inherited disorders worldwide. Accurate analysis of hemoglobin variants is critical for diagnosis of hemoglobinopathies. Although high-performance liquid chromatography and capillary zone electrophoresis are widely used as screening tools, they possess inherent ambiguities that often preclude accurate detection of hemoglobin variants. Our goal was to develop and optimize a sensitive and specific mass spectrometry-based assay for screening and diagnosis of hemoglobinopathies. A catalog of canonical globin-chain specific peptides as well as mutant peptides corresponding to common hemoglobin variants was generated and their corresponding “heavy” synthetic peptide versions were used as internal standards for quantification and calculation of globin chain ratios. Targeted mass spectrometry analysis was performed by coupling liquid chromatography to a triple quadrupole mass spectrometer, which is the commonest mass spectrometer employed in clinical diagnostics. Dried blood spots from a cohort of 716 individuals (including 211 patients with hemoglobinopathy) were analyzed. The α:β-globin ratios showed a significant difference between normal and β-thalassemia patients, particularly when the disease was homozygous or admixed with structural variants (compound heterozygous). The method presented here permits identification of variants in their homozygous, heterozygous or compound heterozygous states. The intra- and inter-assay precision CV were both <20%. We envision that such mass spectrometry-based assays could be employed as first-line screening assay for hemoglobin variants including sickle cell disease as well as thalassemias.
2025-08-01 | PXD061996 | Pride
Project description:Haemoglobin, the oxygen-carrying molecule of red blood cells, at all stages of development comprises a tetramer of two α-like and two β-like globin chains. In humans and mice the highly conserved α- and β-globin loci contain genes encoding globin chains specifically expressed only during the first trimester of gestation (termed embryonic globins) in addition to the genes encoding globin chains expressed throughout adult life. In humans the β-globin locus also encodes a β-like chain that is expressed throughout the second and third trimesters of development; this is termed γ-globin and complexes with α-globin to form fetal haemoglobin (HbF). The sequential activation and repression of the genes at each of these loci throughout development to maturity is termed haemoglobin switching and is a poorly understood process. α-thalassemia, which results from insufficient production of α-globin, is a major global health problem with several hundred thousand sufferers world-wide. The embryonically expressed ζ-globin, encoded by the gene HBZ (Hba-x in mice), can functionally substitute for α-globin in adult erythroid cells. Reactivation of this gene is consequently likely to ameliorate the symptoms of α-thalassemia in individuals with a severe phenotype. Little is currently known about the regulation of ζ-globin expression in terms of both the trans- and cis-acting regulatory elements responsible for high-levels of expression of this gene during embryonic erythropoiesis and its maintenance in a transcriptionally inactive state throughout adult life. Using ATACseq and NG Capture C and mutant mouse lines this work aims to identify and define the cis-acting regulatory network underlying zeta-globin expression, and define the contribution of each regulatory element.
2021-05-06 | GSE108430 | GEO
Project description:Haemoglobin, the oxygen-carrying molecule of red blood cells, at all stages of development comprises a tetramer of two α-like and two β-like globin chains. In humans and mice the highly conserved α- and β-globin loci contain genes encoding globin chains specifically expressed only during the first trimester of gestation (termed embryonic globins) in addition to the genes encoding globin chains expressed throughout adult life. In humans the β-globin locus also encodes a β-like chain that is expressed throughout the second and third trimesters of development; this is termed γ-globin and complexes with α-globin to form fetal haemoglobin (HbF). The sequential activation and repression of the genes at each of these loci throughout development to maturity is termed haemoglobin switching and is a poorly understood process. α-thalassemia, which results from insufficient production of α-globin, is a major global health problem with several hundred thousand sufferers world-wide. The embryonically expressed ζ-globin, encoded by the gene HBZ (Hba-x in mice), can functionally substitute for α-globin in adult erythroid cells. Reactivation of this gene is consequently likely to ameliorate the symptoms of α-thalassemia in individuals with a severe phenotype. Little is currently known about the regulation of ζ-globin expression in terms of both the trans- and cis-acting regulatory elements responsible for high-levels of expression of this gene during embryonic erythropoiesis and its maintenance in a transcriptionally inactive state throughout adult life. Using ATACseq and NG Capture C and mutant mouse lines this work aims to identify and define the cis-acting regulatory network underlying zeta-globin expression, and define the contribution of each regulatory element.
2021-05-06 | GSE108432 | GEO
Project description:Haemoglobin, the oxygen-carrying molecule of red blood cells, at all stages of development comprises a tetramer of two α-like and two β-like globin chains. In humans and mice the highly conserved α- and β-globin loci contain genes encoding globin chains specifically expressed only during the first trimester of gestation (termed embryonic globins) in addition to the genes encoding globin chains expressed throughout adult life. In humans the β-globin locus also encodes a β-like chain that is expressed throughout the second and third trimesters of development; this is termed γ-globin and complexes with α-globin to form fetal haemoglobin (HbF). The sequential activation and repression of the genes at each of these loci throughout development to maturity is termed haemoglobin switching and is a poorly understood process. α-thalassemia, which results from insufficient production of α-globin, is a major global health problem with several hundred thousand sufferers world-wide. The embryonically expressed ζ-globin, encoded by the gene HBZ (Hba-x in mice), can functionally substitute for α-globin in adult erythroid cells. Reactivation of this gene is consequently likely to ameliorate the symptoms of α-thalassemia in individuals with a severe phenotype. Little is currently known about the regulation of ζ-globin expression in terms of both the trans- and cis-acting regulatory elements responsible for high-levels of expression of this gene during embryonic erythropoiesis and its maintenance in a transcriptionally inactive state throughout adult life. Using ATACseq, ChIP-seq and NG Capture C and mutant mouse lines this work aims to identify and define the cis-acting regulatory network underlying zeta-globin expression, and define the contribution of each regulatory element.
2021-05-18 | GSE174593 | GEO
Project description:Hemoglobinopathies, such as sickle cell disease and β-thalassemia, are common genetic disorders remaining significant global health challenges due to their associated morbidity and mortality. Increasing fetal hemoglobin (HbF) levels has emerged as a promising therapeutic strategy for these disorders. In this study, we report MAZ as a repressor of γ-globin expression in human erythroid cells. Depletion of MAZ in HUDEP-2 and patient-derived β-thalassemia cells leads to significant inductions both of γ-globin mRNA and protein levels, resulting in increased HbF percentages and HbF+ erythroid cells. We demonstrate that MAZ occupies at the MYB promoter. MAZ depletion reduced MYB and BCL11A levels. Restoration of MYB re-silenced the γ-globin levels in MAZ depleted cells. Our findings uncover the MAZ-MYB axis in γ-globin regulation, highlighting MAZ as a potential target to enhance HbF levels in patients with hemoglobin disorders.
2025-11-01 | GSE281501 | GEO
Project description:β-hemoglobinopathies are the most common genetic disorders worldwide. In sickle cell disease (SCD) a single mutation (E6V) in the b-globin (HBB) gene results in dysfunctional hemoglobin protein, while in β-thalassemia, over 300 mutations distributed across the HBB gene are known to reduce the production of β-globin and cause severe anemia. A genetic engineering approach that replaces the whole HBB gene is an ideal strategy to rescue HBB expression for most genotypes but is technically challenging as the insert cannot be homologous to the endogenous gene and codon-optimized, intron-less sequences may not reconstitute adequate HBB levels. Here, we developed a novel approach for a “one-size-fits-all" HBB gene repair strategy using CRISPR-Cas9 which successfully addresses these problems. First, our DNA donor design avoids sequence homology through a diverged HBB coding sequence and second, incorporates heterologous introns from the fetal g-globin gene, further reducing homology to endogenous HBB while mimicking its intron composition. Screening DNA donors with various heterologous globin introns, polyadenylation signals and truncated sequences, identified a heterologous intron DNA donor that highly expresses β-globin and rescued β-globin expression in two in vitro hemoglobinopathy models in hematopoietic stem and progenitor cells (HSPCs). Furthermore, healthy donor HSPCs modified with this HBB gene replacement approach showed successful engraftment in immunodeficient mice at 16 weeks. In summary, we developed a universal HBB gene replacement strategy that results in physiological b-globin production, offering a potential differentiated approach for treating patients with β-thalassemia, SCD or compound heterozygous individuals.
2024-04-01 | GSE229212 | GEO
Project description: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.
2026-02-25 | GSE280004 | GEO