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| Status |
Public on Aug 31, 2015 |
| Title |
Dysregulation of the Transforming Growth Factor Beta Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia [HTA-2_0] |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Ge J, Apicella M, Mills JA, Garçon L, French DL, Weiss MJ, Bessler M, Mason PJ |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Jun 26, 2015 |
| Last update date |
Oct 29, 2018 |
| Contact name |
Jingping Ge |
| Organization name |
Children's Hospital of Philadelphia
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| Department |
Pediatrics
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| Street address |
3615 CivicCenter Blvd, ARC 303
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL17586 |
[HTA-2_0] Affymetrix Human Transcriptome Array 2.0 [transcript (gene) version] |
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| Samples (8)
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| GSM1724248 |
iPSC with a RPS19 muation, biological rep1 |
| GSM1724249 |
iPSC with a RPS19 muation, biological rep2 |
| GSM1724250 |
Corrected RPS19 mutant iPSC, biological rep1 |
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| This SubSeries is part of SuperSeries: |
| GSE70349 |
Dysregulation of the Transforming Growth Factor Beta Pathway in Induced Pluripotent Stem Cells Generated from Patients with Diamond Blackfan Anemia |
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| Relations |
| BioProject |
PRJNA288341 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE70348_RAW.tar |
209.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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