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GSE22292
Mus musculus
18 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The reprogramming of fibroblast cells to induced pluripotent stem (iPS) cells raises the possibility that a somatic cell could be reprogrammed to an alternative differentiated fate without first becoming a stem/progenitor cell. A large pool of fibroblast cells exists in the post-natal heart, yet no single master regulator of direct cardiac reprogramming has been identified. Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c and Tbx5) rapidly and efficiently reprogrammed post-natal cardiac or tail-tip fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously. Fibroblast cells transplanted into mouse hearts one day after transduction of the three factors also differentiated into cardiomyocyte-like cells. These findings demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors. Reprogramming of endogenous or explanted fibroblast cells might provide a source of cardiomyocytes for regenerative approaches.
Publication Title
Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina mouse-6 v1.1 expression beadchip
Description
We demonstrate that Prnp dosage is critical for the maintenance of neuronal homeostasis since both its absence and, more relevantly, its overexpression induce higher sensitivity to kainate (KA) damage. These data correlate with electrophysiological results in freely behaving mutant mice showing an imbalance in activity-dependent synaptic processes, as determined from input/output curves, paired-pulse facilitation, and LTP studies. Gene expression profiling showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission among others were co-regulated in knockout and PrPc overexpressing mice. RT-qPCR analysis of neurotransmission-related genes confirmed GABA-A and AMPA-Kainate receptor subunit transcriptional co-regulation in both Prnp -/- and Tg20 mice. Our results demonstrate that PrPc is necessary for the proper homeostatic functioning of hippocampal circuits, because of its interactions with GABAA and AMPA-Kainate receptors.
Publication Title
Regulation of GABA(A) and glutamate receptor expression, synaptic facilitation and long-term potentiation in the hippocampus of prion mutant mice.
Sample Metadata Fields
Sex
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The liver X receptors (LXRs) are ligand-activated nuclear receptors with established roles in the maintenance of lipid homeostasis in multiple tissues. LXRs exert additional biological functions as negative regulators of inflammation, particularly in macrophages. However, the transcriptional responses controlled by LXRs in other myeloid cells, such as dendritic cells (DC), are still poorly understood. Here we used gain- and loss-of-function models to characterize the impact of LXR deficiency on DC activation programs. Our results identified an LXR-dependent pathway that is important for DC chemotaxis. LXR-deficient mature DCs are defective in stimulus-induced migration in vitro and in vivo. Mechanistically, we show that LXRs facilitate DC chemotactic signaling by regulating the expression of CD38, an ectoenzyme important for leukocyte trafficking. Pharmacological or genetic inactivation of CD38 activity abolished LXR-dependent induction of DC chemotaxis. Using the LDLR-/- mouse model of atherosclerosis, we also demonstrated that hematopoietic CD38 expression is important for the accumulation of lipid-laden myeloid cells in lesions, suggesting that CD38 is a key factor in leukocyte migration during atherogenesis. Collectively, our results demonstrate that LXRs are required for efficient emigration of DCs in response to chemotactic signals during inflammation.
Publication Title
LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 3 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Mouse BMDCs were differentiated from bone marrow by GM-CSF and IL-4 for 9 days.
Publication Title
LXR nuclear receptors are transcriptional regulators of dendritic cell chemotaxis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Adult-onset diseases can be associated with in utero events, but mechanisms for such temporally distant dysregulation of organ function remain unknown. The polycomb histone methyltransferase, Ezh2, stabilizes transcription by depositing repressive histone marks during development that persist into adulthood, but the function of Ezh2-mediated transcriptional stability in postnatal organ homeostasis is not understood. Here, we show that Ezh2 stabilizes the postnatal cardiac gene expression program and prevents cardiac pathology, primarily by repressing the homeodomain transcription factor Six1 in differentiating cardiac progenitors. Loss of Ezh2 in embryonic cardiac progenitors, but not in differentiated cardiomyocytes, resulted in postnatal cardiac pathology, including cardiomyocyte hypertrophy and fibrosis. Loss of Ezh2 caused broad derepression of skeletal muscle genes, including the homeodomain transcription factor Six1, which is expressed in cardiac progenitors but is normally silenced upon cardiac differentiation. Many of the deregulated genes are direct Six1 targets, implying a critical requirement for stable repression of Six1 in cardiac myocytes. Indeed, upon de-repression, Six1 promotes cardiac pathology, as it was sufficient to induce cardiac hypertrophy. Furthermore, genetic reduction of Six1 levels almost completely rescued the pathology of Ezh2-deficient hearts. Thus, repression of a single transcription factor in cardiac progenitors by Ezh2 is essential for stability of the adult heart gene expression program and homeostasis. Our results suggest that epigenetic dysregulation during discrete developmental windows can predispose to adult disease and dysregulated stress responses.
Publication Title
Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
Illumina HiSeq 2500
Description
The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 owing to defective yolk sac and placental vascular development. Analysis of global gene expression revealed Frataxin (Fxn), the gene mutated in Friedreich's ataxia (FRDA), as the most strongly downregulated gene in Ctcfdeficient placental endothelial cells. Moreover, in vitro reporter assays showed that Ctcf activates the Fxn promoter in endothelial cells. Reactive oxygen species (ROS) are known to accumulate in the endothelium of FRDA patients. Importantly, Ctcf deficiency induced ROS-mediated DNA damage in endothelial cells in vitro, and in placental endothelium in vivo. Taken together, our findings indicate that, Ctcf promotes vascular development, and limits oxidative stress in endothelial cells, perhaps through activation of Fxn transcription. These results reveal a function for a Ctcf–Fxn transcriptional pathway in vascular development, and also suggest a potential mechanism for endothelial dysfunction in FRDA. Overall design: Examination of transcriptome profiles of placental endothelial cells isolated from wildtype or ctcf defecient endothelial cells at E9.5
Publication Title
The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 16 Downloadable Samples
- Illumina HiSeq 2500
Description
G9a mediates a transcriptional switch, and activates the Notch pathway to coordinate endothelial cell and trophoblast proliferation to promote vascular maturation in the placenta. Overall design: Examination of global transcriptional profiles in control and mutant placenta labyrinth at 2 developmental stages (E12.5 and 13.5).
Publication Title
G9a controls placental vascular maturation by activating the Notch Pathway.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 16 Downloadable Samples
- Illumina HumanWG-6 v3.0 expression beadchip
Description
Immortalized colonic epithelial progenitor cells derived from normal human colon biopsies express stem cell markers and differentiate in vitro
Publication Title
Immortalized epithelial cells derived from human colon biopsies express stem cell markers and differentiate in vitro.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 25 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background: Chronic myeloid leukemia (CML) is a malignant clonal disorder of the hematopoietic system caused by the expression of the BCR/ABL fusion oncogene. It is well known that CML cells are genetically unstable. However, the mechanisms by which these cells acquire genetic alterations are poorly understood. Imatinib mesylate (IM) is the standard therapy for newly diagnosed CML patients. IM targets the oncogenic kinase activity of BCR-ABL. Objective: To study the gene expression profile of BM hematopoietic cells in the same patients with CML before and one month after imatinib therapy. Methods: Samples from patients with CML were analyzed using Affymetrix GeneChip Expression Arrays. Results: A total of 594 differentially expressed genes, most of which (393 genes) were downregulated, as a result of imatinib therapy were observed. Conclusions: The blockade of oncoprotein Bcr-abl by imatinib could cause a decrease in the expression of key DNA repair genes, and cells try to restore the normal gene expression levels required for cell proliferation and chromosomal integrity.
Publication Title
Imatinib therapy of chronic myeloid leukemia restores the expression levels of key genes for DNA damage and cell-cycle progression.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 17 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Cutaneous squamous tumors rely on autocrine/paracrine loops for proper fitness. Targeting this Achilles heel is therefore considered a potential avenue for patient treatment. However, the mechanisms that engage and sustain such programs during tumor ontogeny are poorly understood. Here, we show that two Rho/Rac activators, the exchange factors Vav2 and Vav3, control the expression of an epithelial autocrine/paracrine program that regulates keratinocyte survival and proliferation as well as the creation of an inflammatory microenvironment. Vav proteins are also critically involved in some of the subsequent autocrine signaling loops activated in keratinocytes. The genetic inactivation of both Vav proteins reduces tumor multiplicity without hampering skin homeostasis, thus suggesting that pan-specific Vav therapies may be useful in skin tumor prevention and treatment.
Publication Title
The Rho exchange factors Vav2 and Vav3 favor skin tumor initiation and promotion by engaging extracellular signaling loops.
Sample Metadata Fields
Specimen part
View Samples