Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA399700 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Analysis of erythroblastic cells differentiated from induced pluripotent stem cells (iPSCs) generated from peripheral blood T lymphocytes of CDA type IV patient. Type IV congenital dyserythropoietic anemia (CDA) is due to a monoallelic mutation at the second zinc finger of KLF1 (c.973G>A). Results provide insight into molecular mechanisms underlying CDA pathogenesis.
2019-03-04 | GSE102985 | GEO
Project description:Congenital Dyserythropoietic Anaemia type 1 (CDA-I) is an inherited anaemia arising primarily from mutations in C15orf41 and CDAN1, however the molecular mechanisms that cause the disease remain to be fully elucidated. We use an in vitro culture system to study multiple stages of erythropoiesis from CD34+ progenitors of patients with CDA-I. Applying a number of techniques, including ATAC-seq, we show that differentiation of CDA-I patient erythroblasts closely matches that of healthy donors during the early and intermediate stages of erythroid differentiation and maturation. However, a defect in terminal erythropoiesis can be observed in the CDA-I patient derived erythroblasts, resulting in a reduction in the number of enucleated erythroid cells.
2020-11-02 | GSE125175 | GEO
Project description:Red blood cell disorders can result in severe anemia. One such disease, congenital dyserythropoietic anemia IV (CDA IV) is caused by heterozygous mutation E325K in the transcription factor KLF1. However, studying the molecular basis of CDA IV is severely impeded by paucity of suitable and adequate quantities of material from anaemic patients and rarity of the disease. We therefore took a novel approach, creating a human cellular disease model system for CDA IV, which accurately recapitulates the disease phenotype. Next, using comparative proteomics we reveal extensive distortion of the proteome and a wide range of disordered biological processes in CDA IV erythroid cells. These include down-regulated pathways governing cell cycle, chromatin separation, DNA repair, cytokinesis, membrane trafficking and global transcription, and upregulated networks governing mitochondria biogenesis. The diversity of such pathways elucidates the spectrum of phenotypic abnormalities that occur with CDA IV and impairment to erythroid cell development and survival, collectively explaining the CDA IV disease phenotype. The data also reveal far more extensive involvement of KLF1 in previously assigned biological processes, along with novel roles in the regulation of intracellular processes not previously attributed to this transcription factor. Overall, the data demonstrate the power of such a model cellular system to unravel the molecular basis of disease and how studying effects of a rare mutation can reveal fundamental biology.
2024-04-29 | GSE226782 | GEO
Project description:Congenital dyserythropoietic anemia type I (CDA-I) is an autosomal recessive disorder marked by ineffective erythropoiesis, abnormal morphology of bone marrow erythroblasts, and iron overload. Most cases of CDA-I are caused by mutations in the CDAN1 gene, which encodes for a ubiquitous protein of unknown function, codanin-1. To study the function of codanin-1 in CDA-I erythroid pathophysiology several erythroid models were developed. Here we show that codanin-1 expression is required for erythroid progenitor development and normal erythroid cell differentiation. Erythroid cells lacking codanin-1 demonstrated morphologic changes similar to that observed in CDA-I. Global gene expression changes after codanin-1 knockdown revealed alterations in a set of key erythroid genes. In particular, the AHSP gene, which showed decreased mRNA expression after codanin-1 knockdown in CD34+ cells, also demonstrated increased codanin-1 occupancy at its gene regulatory region by chromatin immunoprecipitation coupled to high-throughput sequencing. Using cell models recapitulating many features of CDA-I, we have confirmed the importance of codanin-1 during erythroid differentiation and provide mechanistic insight into how loss of codanin-1 expression results in CDA-I.
2022-05-19 | GSE131513 | GEO
Project description:Congenital dyserythropoietic anemia type I (CDA-I) is an autosomal recessive disorder marked by ineffective erythropoiesis, abnormal morphology of bone marrow erythroblasts, and iron overload. Most cases of CDA-I are caused by mutations in the CDAN1 gene, which encodes for a ubiquitous protein of unknown function, codanin-1. To study the function of codanin-1 in CDA-I erythroid pathophysiology several erythroid models were developed. Here we show that codanin-1 expression is required for erythroid progenitor development and normal erythroid cell differentiation. Erythroid cells lacking codanin-1 demonstrated morphologic changes similar to that observed in CDA-I. Global gene expression changes after codanin-1 knockdown revealed alterations in a set of key erythroid genes. In particular, the AHSP gene, which showed decreased mRNA expression after codanin-1 knockdown in CD34+ cells, also demonstrated increased codanin-1 occupancy at its gene regulatory region by chromatin immunoprecipitation coupled to high-throughput sequencing. Using cell models recapitulating many features of CDA-I, we have confirmed the importance of codanin-1 during erythroid differentiation and provide mechanistic insight into how loss of codanin-1 expression results in CDA-I.
2022-05-19 | GSE131510 | GEO
Project description:Congenital dyserythropoietic anaemia (CDA) type IV has been associated with an amino acid substitution, Glu325Lys (E325K), in the transcription factor KLF1. Patients with CDA type IV present with a range of symptoms, including the persistence of nucleated red blood cells (RBCs) in the peripheral blood which reflects the known role for KLF1 within the erythroid cell lineage. The final stages of RBCs maturation and enucleation take place within the erythroblastic island (EBI) niche in close association with EBI macrophages. It is not known whether the detrimental effects of the E325K mutation in KLF1 are restricted to the erythroid lineage or whether deficiencies in macrophages associated with their niche also contribute to the disease pathology. To address this question, we generated iPSC lines genetically modified to express a KLF1-E325K-ERT2 protein that could be activated with 4OH-tamoxifen. We performed bulk RNA-sequencing on macrophages generated from these iPSCs, macrophages generated from one KLF1-E325K-ERT2 iPSC line (iCDA4.1) was compared to macrophages generated from one inducible KLF1-WT-ERT2 (K2) iPSC line which was derived from the same parental iPSCs (SFCi55) as the KLF1-E325K-ERT2 line.
2023-03-31 | GSE228537 | GEO
Project description:Induced pluripotent stem cells (iPSCs) were generated from peripheral blood cells of a patient with ID and differentiated into neurons. Label-free phosphoproteomics was used to assess the phosphorylation of proteins in neurons derived from both patients and healthy controls.
2024-10-23 | PXD057079 |
Project description:Pathogenic NOTCH1 mutations are linked to congenital heart defects. To pinpoint how NOTCH1 deficiency affects cardiac development, we generated homozygous NOTCH1 knockout (N1KO) human induced pluripotent stem cells (iPSCs). We then performed high-throughput RNA-seq to profile differential gene expression in cardiomyocytes (iPSC-CMs) and endothelial cells (iPSC-ECs) derived from wild type (WT) and N1KO iPSCs.
2023-01-26 | GSE195559 | GEO
Project description:Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA synthesis and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication. In cellular pancreatic cancer models, high CDA expression correlated with resistance to DNA-damaging agents. Silencing CDA in patient-derived primary cultures in vitro and in orthotopic xenografts in vivo increased replication stress and sensitized pancreatic adenocarcinoma cells to oxaliplatin. This study sheds light on the role of CDA in pancreatic adenocarcinoma, offering insights into how this tumor type modulates replication stress. These findings suggest that CDA expression could potentially predict therapeutic efficacy and that targeting CDA induces intolerable levels of replication stress in cancer cells, particularly when combined with DNA-targeted therapies
2024-01-24 | GSE253837 | GEO
Project description:Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA synthesis and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication. In cellular pancreatic cancer models, high CDA expression correlated with resistance to DNA-damaging agents. Silencing CDA in patient-derived primary cultures in vitro and in orthotopic xenografts in vivo increased replication stress and sensitized pancreatic adenocarcinoma cells to oxaliplatin. This study sheds light on the role of CDA in pancreatic adenocarcinoma, offering insights into how this tumor type modulates replication stress. These findings suggest that CDA expression could potentially predict therapeutic efficacy and that targeting CDA induces intolerable levels of replication stress in cancer cells, particularly when combined with DNA-targeted therapies
2024-01-24 | GSE253662 | GEO