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Dysregulation of the Transforming Growth Factor Beta Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia [HTA-2_0]

ABSTRACT: Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome with clinical features of red cell aplasia and variable developmental abnormalities. Most affected patients have heterozygous loss of function mutations in ribosomal protein genes but the pathogenic mechanism is still unknown. We generated induced pluripotent stem cells from DBA patients carrying RPS19 or RPL5 mutations. Transcriptome analysis revealed the striking dysregulation of the transforming growth factor beta signaling pathway in DBA lines. Expression of TGF beta target genes, such as TGFBI, BAMBI, COL3A1 and SERPINE1 was significantly increased in the DBA iPSCs. We quantified intermediates in canonical and non-canonical TGF beta pathways and observed a significant increase in the levels of the non-canonical pathway mediator p-JNK in the DBA iPSCs. Moreover, when the mutant cells were corrected by ectopic expression of WT RPS19 or RPL5, levels of p-JNK returned to normal. Surprisingly, nuclear levels of SMAD4, a mediator of canonical TGF beta signaling, were decreased in DBA cells due to increased proteolytic turnover. We also observed the up-regulation of TGF beta 1R, TGF beta 2, CDKN1A and SERPINE1 mRNA, and the significant decrease of GATA1 mRNA in the primitive multilineage progenitors. In summary our observations identify for the first time a dysregulation of the TGF beta pathway in the pathobiology of DBA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE70348 | GEO | 2015/08/31

SECONDARY ACCESSION(S): PRJNA288341

REPOSITORIES: GEO

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Dysregulation of the Transforming Growth Factor Beta Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia [HuEx-1_0]

Project description:Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome with clinical features of red cell aplasia and variable developmental abnormalities. Most affected patients have heterozygous loss of function mutations in ribosomal protein genes but the pathogenic mechanism is still unknown. We generated induced pluripotent stem cells from DBA patients carrying RPS19 or RPL5 mutations. Transcriptome analysis revealed the striking dysregulation of the transforming growth factor beta signaling pathway in DBA lines. Expression of TGF beta target genes, such as TGFBI, BAMBI, COL3A1 and SERPINE1 was significantly increased in the DBA iPSCs. We quantified intermediates in canonical and non-canonical TGF beta pathways and observed a significant increase in the levels of the non-canonical pathway mediator p-JNK in the DBA iPSCs. Moreover, when the mutant cells were corrected by ectopic expression of WT RPS19 or RPL5, levels of p-JNK returned to normal. Surprisingly, nuclear levels of SMAD4, a mediator of canonical TGF beta signaling, were decreased in DBA cells due to increased proteolytic turnover. We also observed the up-regulation of TGF beta 1R, TGF beta 2, CDKN1A and SERPINE1 mRNA, and the significant decrease of GATA1 mRNA in the primitive multilineage progenitors. In summary our observations identify for the first time a dysregulation of the TGF beta pathway in the pathobiology of DBA. 6 Total human iPS samples were analyzed, including 2 wild type samples, 2 DBA samples with a RPS19 mutation, and 2 DBA samples with a RPL5 mutation. We generated the following pairwise comparisons using Partek Softare : RPS19 <WT; RPL5<WT. Genes with an FDR≤5% and a fold-change ≥2 were selected.

2015-08-31 | E-GEOD-70347 | biostudies-arrayexpress

Dysregulation of the Transforming Growth Factor Beta Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia [HTA-2_0]

Project description:Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome with clinical features of red cell aplasia and variable developmental abnormalities. Most affected patients have heterozygous loss of function mutations in ribosomal protein genes but the pathogenic mechanism is still unknown. We generated induced pluripotent stem cells from DBA patients carrying RPS19 or RPL5 mutations. Transcriptome analysis revealed the striking dysregulation of the transforming growth factor beta signaling pathway in DBA lines. Expression of TGF beta target genes, such as TGFBI, BAMBI, COL3A1 and SERPINE1 was significantly increased in the DBA iPSCs. We quantified intermediates in canonical and non-canonical TGF beta pathways and observed a significant increase in the levels of the non-canonical pathway mediator p-JNK in the DBA iPSCs. Moreover, when the mutant cells were corrected by ectopic expression of WT RPS19 or RPL5, levels of p-JNK returned to normal. Surprisingly, nuclear levels of SMAD4, a mediator of canonical TGF beta signaling, were decreased in DBA cells due to increased proteolytic turnover. We also observed the up-regulation of TGF beta 1R, TGF beta 2, CDKN1A and SERPINE1 mRNA, and the significant decrease of GATA1 mRNA in the primitive multilineage progenitors. In summary our observations identify for the first time a dysregulation of the TGF beta pathway in the pathobiology of DBA. 8 Total samples were analyzed, including 4 wild type samples, 2 RPS19 mutant samples, 2 corrected RPS19 mutant samples. We generated the following pairwise comparisons using Partek Softare : RPS19 mutant<WT; RPS19 mutant<corrected RPS19 mutant. Genes with an FDR?5% and a fold-change ?2 were selected.

2015-08-31 | E-GEOD-70348 | biostudies-arrayexpress

Dysregulation of the Transforming Growth Factor Beta Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia [HuEx-1_0]

2015-08-31 | GSE70347 | GEO

Transcription profiling of mouse B lymphoma derived A20 cells - effects of JNK on TGF-beta responses of

Project description:TGF-beta plays multiple functions in a board range of cellular responses such as proliferation, differentiation, motility and survival by activating several cellular signaling pathways, including Smads and MAP kinases (Erk, JNK and p38). In particular, TGF-beta can activate pro- or anti-apoptotic signals depending on the target cells. We found that blockage of JNK activation sensitized mouse B lymphoma derived A20 cells to TGF-beta-induced apoptosis. These results suggest that TGF-beta activate JNK to inhibit the activation of death signal that is simultaneously activated by TGF-beta. We used microarrays to gain insight into the effects of JNK inhibition on gene expression in TGF-b-stimulated A20 cells and identified JNK-dependent TGF-beta inducible genes. Experiment Overall Design: The following six samples were prepared: untreated A20 cells (non-stimulated, DMSO): A20 cells cultured with SP600125 for 24 h (non-stimulated, SP600125): A20 cells stimulated with TGF-beta for 12 h (TGF-beta 12 h, DMSO) and 24 h (TGF-beta 24 h, DMSO): and A20 cells stimulated with TGF-beta in the presence of SP600125 for 12 h (TGF-beta 12 h, SP600125) and 24 h (TGF-beta 24 h, SP600125), respectively. Total RNA was prepared and hybridized to the Affymetrix Mouse Genome 430 2.0 array. Genes whose expression was increased by more than 2-fold at either 12 or 24 h after TGF-beta stimulation were identified as TGF-beta inducible genes. Amongst them, we identified genes whose induction levels were reduced by more than 75% by co-treatment with the JNK inhibitor SP600125.

2008-06-15 | E-GEOD-7503 | 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.

2011-06-29 | GSE22645 | GEO

Effects of JNK on TGF-beta responses of mouse B lymphoma derived A20 cells

2007-08-01 | GSE7503 | GEO

ChIP-seq of cholangiocytes treated with TGFbeta

Project description:TGF beta has profound effects on global gene expression changes. To understand the epigenetic mechanisms associated with TGF beta stimulation, we performed ChIP-seq of cholangiocytes to understand the changes in histone modifications associated with TGF beta. We choose H3K27ac and H3K9ac, histone modification associated with gene expression. These histone modifications were correlated with SMAD3 occupancy, which is a canonical downstream mediator of TGF beta signaling.

2020-02-20 | GSE145250 | GEO

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)

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

Transcriptome Analysis Reveals a Comprehensive Regulatory Network Involved in the Zebrafish Model of Diamond-Blackfan Anemia from RPL5 Deficiency [RNA-Seq]

Project description:In this study, we generated a zebrafish model of DBA with RPL5 morphants and implemented high-throughput RNA-seq and miRNA-seq to identify key genes, lncRNAs, and miRNAs during zebrafish development and hematopoiesis. We found that RPL5 is required for both primitive and definitive hematopoiesis processes that are partially mediated by the P53 pathway. Several genes such as cirh1a, noc2l, tars, and nol6 and miRNAs such as dre-miR-10a*, dre-miR-722, dre-miR-737, and dre-miR-142a-3p were significantly deregulated, and these changes may play a crucial role in hematopoiesis, ribosome biogenesis and development process. We also characterized the lncRNome in zebrafish with RPL5 deficiency. By constructing a comprehensive regulatory network, we identified central node genes in the network connected to the P53 pathway, almost all of which were targeted by the significantly deregulated miRNAs listed above. Our results therefore establish a regulatory network for critical genes and miRNAs involved in the RPL5-deficient zebrafish model and provide a comprehensive basis for the molecular pathogenesis of RPL5-mediated DBA and other ribosomopathies.

2017-02-10 | GSE58346 | GEO

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