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GSE45285
Mus musculus
8 Downloadable Samples
Illumina MouseRef-8 v2.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus, Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina MouseRef-8 v2.0 expression beadchip
Description
Protein Arginine MethylTransferase 5 (PRMT5) is known to mediate epigenetic control on chromatin and to functionally regulate components of the splicing machinery. In this study we show that selective deletion of PRMT5 in different organs leads to cell cycle arrest and apoptosis. At the molecular level, PRMT5 depletion results in reduced methylation of Sm proteins, aberrant constitutive splicing and in the Alternative Splicing (AS) of specific mRNAs. We identify Mdm4 as one of these mRNAs, which due to its weak 5-Donor site, acts as a sensor of splicing defects and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in PRMT5 conditional knockout mice. Our data demonstrate a key role of PRMT5, together with p53, as guardians of the transcriptome. This will have fundamental implications in our understanding of PRMT5 activity, both in physiological conditions, as well as pathological conditions, including cancer and neurological diseases.
Publication Title
Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Constitutively active MYC and reactivated telomerase often co-exist in cancers. While the reactivation of telomerase is thought to be essential for replicative immortality, MYC, in conjunction with co-factors, confers several growth advantages to cancer cells. However, it is unclear which co-factors sustain elevated MYC activity in tumors . Here, we identify TERT, the catalytic subunit of telomerase, as a novel regulator of MYC stability in cancers. Binding of TERT to MYC stabilizes its levels on chromatin, contributing to either activation or repression of its target genes. Mechanistically, TERT regulates MYC ubiquitination and stability, and this effect of TERT is independent of its role on telomeres. Genetic inhibition and knocking out of TERT phenocopied the loss of MYC, resulting in reduced disease burden of early- and late-stage MYC-driven murine lymphomas. Conversly, the ectopic expression of TERT could substitute for reduced MYC in these functions. Finally we show that TERT null mice, unlike Terc null mice, show delayed onset of MYC induced lymphomagenesis. Accordingly, inhibiting TERT function in primary human leukemia cells blocked the expression of MYC targets, while Terc depletion had no effects . Based on our data, we conclude that the re-expression of TERT, a direct MYC target in tumors, provides a feed-forward mechanism to potentiate MYC-dependent oncogenesis.
Publication Title
Telomerase regulates MYC-driven oncogenesis independent of its reverse transcriptase activity.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload.
Publication Title
The AP-1 transcription factor c-Jun prevents stress-imposed maladaptive remodeling of the heart.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina human-6 v2.0 expression beadchip
Description
The new official nomenclature subdivides human monocytes into three subsets, classical (CD14++CD16-), intermediate (CD14++CD16+) and nonclassical (CD14+CD16+). Here, we comprehensively define relationships and unique characteristics of the three human monocyte subsets using microarray and flow cytometry analysis. Our analysis revealed that the intermediate and nonclassical monocyte subsets were most closely related. For the intermediate subset, majority of genes and surface markers were expressed at an intermediary level between the classical and nonclassical subset. There features therefore indicate a close and direct lineage relationship between the intermediate and nonclassical subset. From gene expression profiles, we define unique characteristics for each monocyte subset. Classical monocytes were functionally versatile, due to the expression of a wide range of sensing receptors and several members of the AP-1 transcription factor family. The intermediate subset was distinguished by high expression of MHC class II associated genes. The nonclassical subset were most highly differentiated and defined by genes involved in cytoskeleton rearrangement that explains their highly motile patrolling behavior in vivo. Additionally, we identify unique surface markers, CLEC4D, IL-13RA1 for classical, GFRA2, CLEC10A for intermediate and GPR44 for nonclassical. Our study hence defines the fundamental features of monocyte subsets necessary for future research on monocyte heterogeneity.
Publication Title
Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 21 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Adult stem cells residing within tubular glands of the corpus epithelium are believed to fuel daily tissue renewal, but their identity remains controversial. Lgr5, marks both homeostatic stem cells and reserve stem cells in multiple tissues. Here, we report Lgr5 expression in a subpopulation of chief cells in mouse and human corpus glands. Using a new, non-variegated Lgr5-2A-CreERT2 mouse model, we show by cell fate mapping that Lgr5-expressing chief cells do not behave as corpus stem cells under homeostatic conditions, but are recruited to function as stem cells to effect epithelial renewal following injury. In vivo ablation of the Lgr5+ cells severely impairs epithelial homeostasis in the corpus, indicating an essential role in maintaining the resident stem cell pool. We additionally define the Lgr5+ chief cells as a major cell of origin of gastric metaplasia. These findings reveal clinically relevant insights into tissue homeostasis, repair and cancer in the corpus.
Publication Title
No associated publication
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 127 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip (controls added)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 71 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip (controls added)
Description
Mesenchymal stromal cells (MSCs) can be obtained from several sources and the significant differences in their properties, makes it crucial to investigate the differentiation potential of MSCs from different sources to determine the optimal source of MSCs. We investigated if this biological heterogeneity in MSCs from different sources results in different mechanisms for their differentiation. In this study, we compared the gene expression patterns of phenotypically defined MSCs derived from three ontogenically different sources: Embryonic stem cells (hES-MSCs), Fetal limb (Flb-MSCs) and Bone Marrow (BM-MSCs). Differentially expressed genes between differentiated cells and undifferentiated controls were compared across the three MSC sources. We found minimal overlap in differential gene expression (5-16%) among the three sources. Flb-MSCs were similar to BM-MSCs based on differential gene expression patterns. Pathway analysis of the differentially expressed genes using Ingenuity Pathway Analysis (IPA) revealed a large variation in the canonical pathways leading to MSC differentiation. The similar canonical pathways among the three sources were lineage specific. The Flb-MSCs showed maximum overlap of canonical pathways with the BM-MSCs, indicating that the Flb-MSCs is an intermediate source between the less specialised hES-MSC source and the more specialised BM-MSC source. The source specific pathways prove that MSCs from the three ontogenically different sources use different biological pathways to obtain similar differentiation outcomes. Thus our study advocates the understanding of biological pathways to obtain optimal sources of MSCs for various clinical applications.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 56 Downloadable Samples
- Illumina HumanRef-8 v3.0 expression beadchip (controls added)
Description
Mesenchymal stromal cells (MSCs) can be obtained from several sources and the significant differences in their properties, makes it crucial to investigate the differentiation potential of MSCs from different sources to determine the optimal source of MSCs. We investigated if this biological heterogeneity in MSCs from different sources results in different mechanisms for their differentiation. In this study, we compared the gene expression patterns of phenotypically defined MSCs derived from three ontogenically different sources: Embryonic stem cells (hES-MSCs), Fetal limb (Flb-MSCs) and Bone Marrow (BM-MSCs). Differentially expressed genes between differentiated cells and undifferentiated controls were compared across the three MSC sources. We found minimal overlap in differential gene expression (5-16%) among the three sources. Flb-MSCs were similar to BM-MSCs based on differential gene expression patterns. Pathway analysis of the differentially expressed genes using Ingenuity Pathway Analysis (IPA) revealed a large variation in the canonical pathways leading to MSC differentiation. The similar canonical pathways among the three sources were lineage specific. The Flb-MSCs showed maximum overlap of canonical pathways with the BM-MSCs, indicating that the Flb-MSCs is an intermediate source between the less specialised hES-MSC source and the more specialised BM-MSC source. The source specific pathways prove that MSCs from the three ontogenically different sources use different biological pathways to obtain similar differentiation outcomes. Thus our study advocates the understanding of biological pathways to obtain optimal sources of MSCs for various clinical applications.
Publication Title
No associated publication
Sample Metadata Fields
Specimen part
View Samples