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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome profiling of c-Kit+ hematopoietic stem and progenitor cells enriched from 10-week-old wild-type and Rps19R67∆/R67∆ mutant mice.

ABSTRACT: This RNA sequencing experiment is part of the study "Preclinical animal model of Diamond-Blackfan anemia with single amino acid mutation of ribosomal protein Rps19". A mouse model with arginine 67 mutation of ribosomal protein Rps19 develops features characteristic of human Diamond-Blackfan anemia, a rare bone marrow failure syndrome. These include hematologic dysfunctions, early onset growth delay, intrinsic anemia, severe craniofacial, skeletal, urogenital, cardiovascular, and cerebral abnormalities leading to premature lethality during the adolescence of the mouse. This model exhibits cell intrinsic activation of the Trp53 signaling pathway in hematopoietic stem cells (HSCs) leading to reduced erythroid lineage development that may be rescued after inactivation of the tumor suppressor Trp53. Using preliminary RNA sequencing study we identify a set of non-canonical components of the p53 signaling pathway which with high likelihood mediate the wide range of pathologies associated with DBA, the experiment if followed up by single cell transcriptome analysis of bone marrow hematopoietic progenitors and RNA sequencing of E14.5 fetal liver from wild-type control and Rps19R67∆/R67∆, Rps19R67∆/R67∆ Trp53−/− and Trp53−/− mutant embryos.

INSTRUMENT(S): NextSeq 550

ORGANISM(S): Mus musculus

SUBMITTER: Juraj Kokavec

PROVIDER: E-MTAB-12447 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Single cell transcriptomic analysis of bone marrow hematopoietic stem and progenitors cells isolated from 10-week-old wild-type control, Rps19R67∆/R67∆, Rps19R67∆/R67∆ Trp53−/− and Trp53−/− mutant mice.

Project description:This single cell transcriptome sequencing experiment is part of the study \\"Preclinical animal model of Diamond-Blackfan anemia with single amino acid mutation of ribosomal protein Rps19\\". A mouse model with this mutation develops features characteristic of human Diamond-Blackfan anemia, a rare bone marrow failure syndrome, including hematologic dysfunctions, early onset growth delay, intrinsic anemia, severe craniofacial, skeletal, urogenital, cardiovascular, and cerebral abnormalities leading to premature lethality during the adolescence of the mouse. This DBA mouse model exhibits cell intrinsic activation of the Trp53 signaling pathway in hematopoietic stem cells (HSCs) leading to reduced erythroid lineage development that may be rescued after inactivation of the tumor suppressor Trp53. The study uncovers that the development of the DBA phenotype significantly involves non-canonical components of the p53 signaling pathway in the etiopathogenesis of DBA with the Rps19R67∆ mutation leading to the disrupted hematopoietic hierarchy starting at the stage of short-term repopulating stem cells and the central role of induced Trp53 expression and upregulation of its non-canonical targets in the mediation of neural crest lineage deficiency-mediated development of craniofacial malformations in this model.

2023-05-01 | E-MTAB-12446 | biostudies-arrayexpress

RNAseq of E14.5 fetal liver isolated from wild-type control, Rps19R67∆/R67∆, Rps19R67∆/R67∆ Trp53−/− and Trp53−/− mutant embryos.

Project description:This RNA sequencing experiment is part of the study \\"Preclinical animal model of Diamond-Blackfan anemia with single amino acid mutation of ribosomal protein Rps19\\". A mouse model with conserved arginine 67 deletion of ribosomal protein Rps19 mutation develops features characteristic of human Diamond-Blackfan anemia, a rare bone marrow failure syndrome, including hematologic dysfunctions, early onset growth delay, intrinsic anemia, severe craniofacial, skeletal, urogenital, cardiovascular, and cerebral abnormalities leading to premature lethality during the adolescence of the mouse. This DBA mouse model exhibits cell intrinsic activation of the Trp53 signaling pathway in hematopoietic stem cells (HSCs) leading to reduced erythroid lineage development that may be rescued after inactivation of the tumor suppressor Trp53. The E14.5 fetal liver transcriptome analysis study confirms the involvement of non-canonical components of the p53 signaling pathway in the etiopathogenesis of DBA, manifested already during fetal development, consistent with the early onset of DBA-like phenotypes in mouse embryos as well as development of the disease in neonatal human patients. These results confirm our previous findings in adult hematopoietic progenitors as well as indicate that the development of DBA occurs well into the fetal development in both humans and our mouse model.

2023-05-31 | E-MTAB-12448 | biostudies-arrayexpress

Mechanism of action of RPS19R62W mutation in Diamond-Blackfan Anemia (DBA)

Project description:RPS19 mutations are the most common cause of the human disorder Diamond Blackfan Anemia. The R62W mutation was hypothesized to act in a dominant negative fashion and mice expressing RPS19R62W have many of the characteristics of Diamond Blackfan Anemia. Diamond-Blackfan Anemia (DBA), is an inherited erythroblastopenia associated with mutations in at least 8 different ribosomal protein genes. Mutations in the gene encoding Ribosomal Protein S19 (RPS19) have been identified in ~25% of DBA families. Most of these mutations disrupt either the translation or stability of the RPS19 protein and are predicted to cause DBA by haploinsufficiency. However, approximately ~30% of RPS19 mutations are missense mutations that do not alter the stability of the RPS19 protein and are hypothesized to act by a dominant negative mechanism. To formally test this hypothesis, we generated a transgenic mouse model expressing an RPS19 mutation in which an Arginine residue is replaced with a Tryptophan residue at codon 62 (RPS19R62W). Constitutive expression of RPS19R62W in developing mice was lethal. Conditional expression of RPS19R62W resulted in growth retardation, a mild anemia with reduced numbers of erythroid progenitors and significant inhibition of terminal erythroid maturation, similar to DBA. RNA profiling demonstrated over 700 dysregulated genes belonging to the same pathways that are disrupted in RNA profiles of DBA patient cells. The samples compared are RNA extracted from CD71 positive erythroblasts sorted from the bone marrow of wild type mice and mice expressing a mutant RPS19 (RPS19R62W) transgene

2011-06-29 | E-GEOD-22645 | biostudies-arrayexpress

Mechanism of action of RPS19R62W mutation in Diamond-Blackfan Anemia (DBA)

2011-06-29 | GSE22645 | GEO

Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia.

Project description:Transcriptome profile of highly purified multipotential (P), erythroid (E), and myeloid (M) bone marrow progenitors from three RPS19 mutated Diamond-Blackfan anemia and six control human subjects. Two group comparison of sex and age matched subjects. Bone marrow progenitors, gene expression profiling, Diamond-Blackfan anemia, RPS19

2012-10-16 | E-GEOD-41599 | biostudies-arrayexpress

Analysis of the interactome of RPS19 mutants

Project description:Ribosomal protein S19 (RPS19) is a 16-kDa protein found mainly as a component of the ribosomal 40 S subunit. Its mutations are responsible for Diamond Blackfan anemia, a congenital disease characterized by defective erythroid progenitor maturation. To clarify the function of RPS19, we compare the interactome of RPS19 wilde type and their two mutant proteins: RPS19-R62W and RPS19- R101H. Mutations R62W and R101H impair RPS19 ability to associate with the ribosome. We found striking differences between the interactomes of wild type and mutant RPS19 proteins. In particular, mutations abolish interactions with proteins having splicing, translational and helicase activity, thus confirming the role of RPS19 in RNA processing/metabolism and translational control.

2014-08-11 | PXD000640 | Pride

RPS19 binding with and without Diamond-Blackfan anemia variants

Project description:We found that endogenously expressed RPS19 binds evolutionarily constrained intronic elements. By assessing overexpression of WT RPS19 and RPS19 harboring the most common Diamond-Blackfan anemia missense mutations, we confirmed that disease-relevant mutations alter RPS19 binding preferences in human cells.

2023-02-14 | GSE224998 | GEO

Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia.

2012-10-16 | GSE41599 | GEO

Gene expression analysis from erythroid progenitors of patients with Diamond-Blackfan anemia

Project description:Gene expression analysis from erythroid progenitors (CD34+/CD71(high)/CD45- mononuclear cells from the bone marrow) of patients with Diamond-Blackfan anemia (due to RPS19 mutations) and control individuals.

2014-02-28 | GSE41817 | GEO

Gene expression analysis from erythroid progenitors of patients with Diamond-Blackfan anemia

2014-02-28 | E-GEOD-41817 | biostudies-arrayexpress

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