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SRP103188
Homo sapiens
13 Downloadable Samples
Description
Here we propose the direct conversion of human somatic cells into naive induced pluripotent cells (niPSC). Dataset: 7 expanded niPSC lines (4 from BJ cells, 1 from HFF-1, 1 from WI38, 1from IMR90), 1 freshly-isolated primary colonies of niPSC from BJ, 1 established naive embryonic line H9, 1 primed induced pluripotent cell line (from BJ), 1 sample of BJ fibroblasts, 1 sample of WI38 fibroblasts, 1 sample IMR90 fibroblasts.
Publication Title
Direct generation of human naive induced pluripotent stem cells from somatic cells in microfluidics.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 3 Downloadable Samples
Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
In addition to lipid second messengers derived from the plasma membrane, increasing evidence supports the existence of nuclear lipid-dependent signaling networks. Diacylglycerol is a key second messenger, generated at the nuclear level, which is metabolized by diacylglycerol kinases (DGKs). It has been demonstrated that nuclear DGK- negatively regulates cell cycle progression. The aim of this study was to identify key determinants of nuclear DGK--dependent cell cycle arrest in C2C12 mouse myoblasts. Using DNA microarrays, Real-Time RT-PCR and western blot, we demonstrated that nuclear DGK- downregulated the expression of cyclin D1 and increased the expression of TIS21/BTG2/PC3, a transcriptional regulator of cyclin D1 with a strong anti-proliferative function. Overexpression of TIS21/BTG2/PC3 blocked the cells in G1 phase of the cell cycle and decreased the levels of Ser807/811 phosphorylated retinoblastoma protein, similarly to overexpression of DGK-. Moreover, during myogenic differentiation of C2C12 cells, we showed an increase of TIS21/BTG2/PC3 expression and a decrease in cyclin D1 levels. siRNA downregulation of TIS21/BTG2/PC3 impaired myogenic differentiation by opposing cell cycle arrest. In summary, these data identify TIS21/BTG2/PC3 and cyclin D1 as downstream effectors of the nuclear DGK- and highlight the importance of this DGK isoform in the regulation of myoblast proliferation and differentiation.
Publication Title
TIS21/BTG2/PC3 and cyclin D1 are key determinants of nuclear diacylglycerol kinase-zeta-dependent cell cycle arrest.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 7 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
The thrombopoietin/MPL axis is activated in the Gata1<sup>low</sup> mouse model of myelofibrosis and is associated with a defective RPS14 signature.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 1 Downloadable Sample
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Myelofibrosis (MF) is caused by genetic abnormalities involving the thrombopoietin (TPO)/MPL/JAK2 axis. Furthermore MF patients have elevated serum TPO levels. MF is also associated with reduced GATA1 content in MK suggesting that this abnormality represents a phenotypic modifier. In 2014, Dr. Crispino suggested that in MF abnormal TPO signaling induces a ribosomal deficiency hampering GATA1 mRNA translation in MK. Support for MK GATA1 deficiency as phenotypic modifier in MF was provided by the observation that mice carrying the Gata1low mutation reducing Gata1 transcription in MK develop myelofibrosis. Since reduced RBC half-life subject these mice to continuous erythroid stress, we investigated the TPO/Mpl axis in this model. In Gata1low and wild-type mice, TPO mRNA was expressed by bone marrow (BM), spleen and liver. The greatest expression (by 300-fold) was detected in liver. Gata1low livers expressed TPO mRNA levels 6-fold greater than wild-type livers. TPO protein was detected in BM, spleen, liver and peritoneum washes and plasma. The greatest levels where detected in plasma. Gata1low plasma contained TPO levels 2-fold lower than wild-type plasma, but 2-times greater than plasma from bleed wild-type mice and Mplnull mice with similar thrombocytopenia, suggesting that TPO is overproduced in Gata1low mice. JAK2 and STAT5 were easily detected in Gata1low BM bur barely detectable in wild-type BM, suggesting that in the former MPL is prompt to signaling activation. Furthermore, Gata1low LSK expressed levels of Mpl mRNA 3-times greater than wild-type cells but expressed cell-surface levels of MPL 2-times lower than wild-type cells and similar to those on LSK from TPO-treated wild-type mice, suggesting that MPL is down-modulated in Gata1low LSK. The Crispinos hypothesis that in MF activation of TPO/MPL/JAK2 induces a ribosomal deficiency hampering GATA1 mRNA translation and the realization that this axis is activated in Gata1low mice made us question the original hypothesis that reduced content of GATA1 in Gata1low MK results from deletion of lineage-specific enhancers. Microarray analyses indeed identified that Gata1low BM express a discordant ribosome signature including reduced expression of RPS24 and RPS36A, two genes mutated in Diamond Blackfan Anemia, a disease characterized by inefficient GATA1 mRNA translation. Electron microscopy identified that the cytoplasm of Gata1low MK contained poorly developed endoplasmic reticulum with rare polysomes. In conclusion, these results validate the Gata1low model as a MF model by indicating that these mice express an activated TPO/MPL axis and an abnormal ribosomal signature which may reduce efficiency of Gata1 mRNA translation.
Publication Title
The thrombopoietin/MPL axis is activated in the Gata1<sup>low</sup> mouse model of myelofibrosis and is associated with a defective RPS14 signature.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 6 Downloadable Samples
Illumina MouseWG-6 v2.0 expression beadchip
Description
Myelofibrosis (MF) is caused by genetic abnormalities involving the thrombopoietin (TPO)/MPL/JAK2 axis. Furthermore MF patients have elevated serum TPO levels. MF is also associated with reduced GATA1 content in MK suggesting that this abnormality represents a phenotypic modifier. In 2014, Dr. Crispino suggested that in MF abnormal TPO signaling induces a ribosomal deficiency hampering GATA1 mRNA translation in MK. Support for MK GATA1 deficiency as phenotypic modifier in MF was provided by the observation that mice carrying the Gata1low mutation reducing Gata1 transcription in MK develop myelofibrosis. Since reduced RBC half-life subject these mice to continuous erythroid stress, we investigated the TPO/Mpl axis in this model. In Gata1low and wild-type mice, TPO mRNA was expressed by bone marrow (BM), spleen and liver. The greatest expression (by 300-fold) was detected in liver. Gata1low livers expressed TPO mRNA levels 6-fold greater than wild-type livers. TPO protein was detected in BM, spleen, liver and peritoneum washes and plasma. The greatest levels where detected in plasma. Gata1low plasma contained TPO levels 2-fold lower than wild-type plasma, but 2-times greater than plasma from bleed wild-type mice and Mplnull mice with similar thrombocytopenia, suggesting that TPO is overproduced in Gata1low mice. JAK2 and STAT5 were easily detected in Gata1low BM bur barely detectable in wild-type BM, suggesting that in the former MPL is prompt to signaling activation. Furthermore, Gata1low LSK expressed levels of Mpl mRNA 3-times greater than wild-type cells but expressed cell-surface levels of MPL 2-times lower than wild-type cells and similar to those on LSK from TPO-treated wild-type mice, suggesting that MPL is down-modulated in Gata1low LSK. The Crispinos hypothesis that in MF activation of TPO/MPL/JAK2 induces a ribosomal deficiency hampering GATA1 mRNA translation and the realization that this axis is activated in Gata1low mice made us question the original hypothesis that reduced content of GATA1 in Gata1low MK results from deletion of lineage-specific enhancers. Microarray analyses indeed identified that Gata1low BM express a discordant ribosome signature including reduced expression of RPS24 and RPS36A, two genes mutated in Diamond Blackfan Anemia, a disease characterized by inefficient GATA1 mRNA translation. Electron microscopy identified that the cytoplasm of Gata1low MK contained poorly developed endoplasmic reticulum with rare polysomes. In conclusion, these results validate the Gata1low model as a MF model by indicating that these mice express an activated TPO/MPL axis and an abnormal ribosomal signature which may reduce efficiency of Gata1 mRNA translation.
Publication Title
The thrombopoietin/MPL axis is activated in the Gata1<sup>low</sup> mouse model of myelofibrosis and is associated with a defective RPS14 signature.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Clariom S Human array (clariomshuman)
Description
Pediatric Acute Myeloid Leukemia (AML) is an aggressive and poor prognosis malignancy for which there are few effective targeted approaches, despite the numerous genetic alterations, including MLL gene rearrangements (MLL-r). The histone methyltransferase DOT1L is involved in supporting proliferation of MLL-r cells, for which a target inhibitor, Pinometostat, has been evaluated in a clinical trial recruiting pediatric MLL-r leukemic patients. However, modest clinical effects have been reported. Recent studies reported that additional leukemia subtypes lacking MLL-r are sensitive to DOT1L inhibition. Here we report that targeting DOT1L with Pinometostat sensitizes pediatric AML cells to further treatment with the multi-kinase inhibitor Sorafenib, irrespectively of MLL-r. DOT1L pharmacologic inhibition induces AML cell differentiation and modulated expression of genes with relevant roles in cancer development. Such modifications in transcriptional program impact on further treatments, inducing a strong sensitization to Sorafenib, with increased apoptosis and growth suppression of both AML cell lines and primary pediatric AML cells with diverse genotypes. We used microarrays to define differential regulation of gene expression in AML cell lines with or without MLL gene rearrangements following pharmacologic inhibition of DOT1L.
Publication Title
Inhibition of Methyltransferase DOT1L Sensitizes to Sorafenib Treatment AML Cells Irrespective of <i>MLL</i>-Rearrangements: A Novel Therapeutic Strategy for Pediatric AML.
Sample Metadata Fields
Treatment
View Samples- Mus musculus
- 22 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
In order to understand the consequences of miR-210 blocking on the ischemia response, the transcriptomic changes were investigated by microarray technology in gastrocnemius muscles of ANTI-210 and SCR treated mice, 7 days after ischemia.
Publication Title
Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Myotonic Dystrophy Type-2 (DM2) is an autosomal dominant disease caused by the expansion of a CCTG tetraplet repeat. It is a multisystemic disorder, affecting skeletal muscles, the heart, the eye, the central nervous system and the endocrine system.
Publication Title
Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2.
Sample Metadata Fields
Sex, Age, Specimen part, Disease, Disease stage
View Samples- Mus musculus, Homo sapiens
- 16 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip, Illumina MouseRef-8 v2.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Liver X receptors inhibit proliferation of human colorectal cancer cells and growth of intestinal tumors in mice.
Sample Metadata Fields
Age, Specimen part
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
MicroRNAs (miRNAs) are small non-protein-coding RNAs that are incorporated into the RNA-induced silencing complex (RISC) and inhibit gene expression by regulating the stability and/or the translational efficiency of target mRNAs. Previously, we demonstrated that miR-210 is a key player of endothelial cell (EC) response to hypoxia, modulating EC survival, migration and ability to form capillary like-structures. Moreover, the receptor tyrosine kinase ligand Ephrin-A3 was identified as one functionally relevant target. Since each miRNA regulates hundreds of mRNAs, different approaches were combined to identify new miR-210 targets: a Using target prediction software, 32 new miR-210 potential targets were identified. b The proteomic profiling of miR-210 over-expressing ECs identified 11 proteins that were specifically inhibited by miR-210, either directly or indirectly. c Affymetrix based gene expression profiles identified 51 genes that were both down-modulated by miR-210 over-expression and de-repressed when miR-210 was blocked. Surprisingly, only few genes identified either by proteomics or transcriptomics were recognized as miR-210 targets by target prediction algorithms. However, a low-stringency pairing research revealed enrichment for miR-210 putative binding sites, raising the possibility that these genes were targeted via non-canonical recognition sequences. To clarify this issue, miR-210-loaded RISC was purified by immuno-precipitation along with its mRNA targets. The presence of Ephrin-A3 mRNA in the complex validated this approach. We found that 32 potential targets were indeed enriched in miR-210-loaded RISC, and thus can be considered as genuine miR-210 targets. In keeping with this conclusion, we were able to further validate a sub-set of them by 3UTR-reporter assays. Gene ontology analysis of the targets confirmed the known miR-210 activity in differentiation and cell cycle regulation, highlighting new functions such as involvement in RNA processing, DNA binding, development, membrane trafficking and amino acid catabolism. In conclusion, we validated a multidisciplinary approach for miRNAs target identification and indicated novel molecular mechanisms underpinning miR-210 role in EC response to hypoxia.
Publication Title
An integrated approach for experimental target identification of hypoxia-induced miR-210.
Sample Metadata Fields
Cell line
View Samples