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GSE146756
Mus musculus
10 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The goal of this study is to uncover the changes in the transcriptome of sensory neurons of the liver kinase B1 (LKB1) knockout
Publication Title
Regulation of axonal morphogenesis by the mitochondrial protein Efhd1.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Technologies allowing for specific regulation of endogenous genes are valuable for the study of gene functions and have great potential in therapeutics. We created the CRISPR-on system, a two-component transcriptional activator consisting of a nuclease-dead Cas9 (dCas9) protein fused with a transcriptional activation domain and single guide RNAs (sgRNAs) with complementary sequence to gene promoters. We demonstrate that CRISPR-on can efficiently activate exogenous reporter genes in both human and mouse cells in a tunable manner. In addition, we show that robust reporter gene activation in vivo can be achieved by injecting the system components into mouse zygotes. Furthermore we show that CRISPR-on can activate the endogenous IL1RN, SOX2, and OCT4 genes. The most efficient gene activation was achieved by clusters of 3 to 4 sgRNAs binding to the proximal promoters suggesting their synergistic action in gene induction. Significantly, when sgRNAs targeting multiple genes were simultaneously introduced into cells, robust multiplexed endogenous gene activation was achieved. Genome-wide expression profiling demonstrated high specificity of the system.
Publication Title
Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 4 Downloadable Samples
IlluminaHiSeq2000
Description
The control of cell identity is orchestrated by transcriptional and chromatin regulators in the context of specific chromosome structures. With the recent isolation of human naive embryonic stem cells (ESCs) representative of the ground state of pluripotency, it is possible to deduce this regulatory landscape in one of the earliest stages of human development. Here we generate cohesin ChIA-PET chromatin interaction data in naive and primed human ESCs and use it to reconstruct and compare the 3D regulatory landscapes of these two stages of early human development. The results reveal shared and stage-specific regulatory landscapes of topological domains and their subdomains, which consist of CTCF-CTCF/cohesin loops and enhancer-promoter/cohesin loops. The enhancer-promoter loop data reveal that genes with key roles in pluripotency are nearly always regulated by one or more super-enhancers, and show that these genes tend to occur in insulated neighborhoods. Our results reveal the key features of the 3D regulatory landscape of early human cells that form the foundation for embryonic development. Overall design: Polyadenylated RNA-seq from naive and primed human embroynic stem cells.
Publication Title
3D Chromosome Regulatory Landscape of Human Pluripotent Cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The retinal pigment epithelium (RPE) provides vital support to photoreceptor cells and its dysfunction is associated with the onset and progression of age-related macular degeneration (AMD). Surgical provision of RPE cells may ameliorate AMD and thus it would be valuable to develop sources of patient-matched RPE cells for this application of regenerative medicine. We describe here the generation of functional RPE-like cells from fibroblasts that represent an important step toward that goal. We identified candidate master transcriptional regulators of RPEs using a novel computational method and then used these regulators to guide exploration of the transcriptional regulatory circuitry of RPE cells and to reprogram human fibroblasts into RPE-like cells. The RPE-like cells share key features with RPEs derived from healthy individuals, including morphology, gene expression and function, and thus represent a step toward the goal of generating patient-matched RPE cells for treatment of macular degeneration.
Publication Title
A Systematic Approach to Identify Candidate Transcription Factors that Control Cell Identity.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
Regulatory T cells (Tregs) expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance1-5; yet, excessive Treg activities suppress anti-tumor immune responses6-8. Compared to resting phenotype Tregs (rTregs) in the secondary lymphoid organs, Tregs in non-lymphoid tissues including solid tumors exhibit an activated Treg (aTreg) phenotype9-11. However, aTreg function and whether its generation can be manipulated to promote tumor immunity without evoking autoimmunity are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg suppression of lymphoproliferative diseases12,13, has an unexpected function in inhibiting aTreg-mediated immune tolerance. We found that aTregs turned over at a slower rate than rTregs, but were not locally maintained in tissues. Transcriptome analysis revealed that aTreg differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic Foxo1 localization, and enhanced Foxo1 phosphorylation at sites of the Akt kinase. Treg-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg homing to non-lymphoid organs, causing CD8+ T cell-mediated autoimmune diseases. Compared to Tregs from healthy tissues, tumor-infiltrating Tregs downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumor-associated Tregs, activate effector CD8+ T cells, and inhibit tumor growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTregs that have a crucial function in suppressing CD8+ T cell responses; and the Foxo signaling pathway in Tregs can be titrated to preferentially break tumor immune tolerance. Overall design: Transcriptome of splenic rTreg (CD4+Foxp3+CD62LhiCD44lo) and aTreg (CD4+Foxp3+CD62LhiCD44lo) were compared. Duplicates from biologically independent animials were used.
Publication Title
Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 16 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
We investigated the DNA methylation and gene expression of 20 chorionic villi samples from early onset preeclampsia placentas to 20 gestational age matched controls. From this we were able to see a widespread disregulation in DNA methylation across a subset of genes in the genome. This may help to elucidate the underlying biological problems that lead to early onset preeclampsia. We noted that there were DNA methylation changes in many genes of importance as well as in different genomic elements such as enhancers.
Publication Title
Widespread DNA hypomethylation at gene enhancer regions in placentas associated with early-onset pre-eclampsia.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Kaposis sarcoma (KS) is the most frequently occurring malignant tumor in patients infected with the human immunodeficiency virus. Recent studies have revealed that infection of vascular endothelial cells with Kaposi's sarcoma-associated herpes virus in vitro results in a lymphatic re-programming of these cells, with potent induction of the lymphatic marker genes podoplanin and VEGFR-3 which is mediated by upregulation of the transcription factor Prox1. However, the potential effects of Prox1 expression on the biology of KS and, in particular, on the aggressive and invasive behavior of KS tumors in vivo have remained unknown. We stably expressed Prox1 cDNA in the two mouse hemangioendothelioma cell lines EOMA and Py-4-1, well-established murine models for kaposiform hemangioendothelioma. Surprisingly, we found that expression of Prox1 was sufficient to induce a more aggressive behavior of tumors growing in syngenic mice, leading to enhanced local invasion into the muscular layer and to cellular anaplasia. This enhanced malignant phenotype was associated with upregulation of several genes involved in proteolysis, cytoskeletal reorganisation and migration. Together, these results indicate that Prox1 plays an important, previously unanticipated role in mediating the aggressive behavior of vascular neoplasms such as Kaposi's sarcoma.
Publication Title
Prox-1 promotes invasion of kaposiform hemangioendotheliomas.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Papillomaviruses (PVs) are able to induce papillomas, premalignant lesions, and carcinomas in a wide variety of species. PVs are classified first based on their host and tissue tropism and then their genomic diversities. A laboratory mouse papillomavirus, MmuPV1 (formerly MusPV), naturally infects NMRI-Foxn1nu/Foxn1nu (nude; T cell deficient) mice. C57BL/6J wild-type mice were not susceptible to MmuPV1 infection; however, immunocompetent, alopecic, S/RV/Cri-ba/ba (bare) mice developed small papillomas at injection sites that regressed. NMRI-Foxn1nu and B6.Cg-Foxn1nu but not NU/J-Foxn1nu mice were susceptible to MmuPV1 infection. B6 congenic strains, but not other congenic strains carrying the same allelic mutations, that lack B- and T-cells, but not B-cells alone, were susceptible to infection, indicating that mouse strain and T-cell deficiency are critical to tumor formation. Although lesions initially observed were exophytic papillomas around the muzzle, exophytic papillomas on the tail and condylomas of the vaginal lining could be induced by experimental infections. On the dorsal skin, locally invasive, poorly differentiated tumors developed with features similar to human trichoblastomas. Transcriptome analysis revealed significant differences between the normal skin in these anatomic sites and in papillomas versus trichoblastomas. The primarily dysregulated genes involved molecular pathways associated with cancer, cellular development, cellular growth and proliferation, cell morphology, and connective tissue development and function. Surprisingly, few of the genes commonly associated with basal cell carcinoma or squamous cells carcinoma were dramatically dysregulated.
Publication Title
Immune status, strain background, and anatomic site of inoculation affect mouse papillomavirus (MmuPV1) induction of exophytic papillomas or endophytic trichoblastomas.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 45 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Barrett's esophagus is characterized by the replacement of squamous epithelium with specialized intestinal metaplastic mucosa. The exact mechanisms of initiation and development of Barrett's metaplasia remain unknown, but a hypothesis of successful adaptation against noxious reflux components has been proposed. To search for the repertoire of adaptation mechanisms of Barrett's metaplasia, we employed high-throughput functional genomic and proteomic methods that defined the molecular background of metaplastic mucosa resistance to reflux. Transcriptional profiling was established for 23 pairs of esophageal squamous epithelium and Barrett's metaplasia tissue samples using Affymetrix U133A 2.0 GeneChips and validated by quantitative real-time polymerase chain reaction. Differences in protein composition were assessed by electrophoretic and mass-spectrometry-based methods. Among 2,822 genes differentially expressed between Barrett's metaplasia and squamous epithelium, we observed significantly overexpressed metaplastic mucosa genes that encode cytokines and growth factors, constituents of extracellular matrix, basement membrane and tight junctions, and proteins involved in prostaglandin and phosphoinositol metabolism, nitric oxide production, and bioenergetics. Their expression likely reflects defense and repair responses of metaplastic mucosa, whereas overexpression of genes encoding heat shock proteins and several protein kinases in squamous epithelium may reflect lower resistance of normal esophageal epithelium than Barrett's metaplasia to reflux components. Despite the methodological and interpretative difficulties in data analyses discussed in this paper, our studies confirm that Barrett's metaplasia may be regarded as a specific microevolution allowing for accumulation of mucosal morphological and physiological changes that better protect against reflux injury.
Publication Title
Molecular defense mechanisms of Barrett's metaplasia estimated by an integrative genomics.
Sample Metadata Fields
Sex, Age
View Samples