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SRP066117
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- Mus musculus
- 2 Downloadable Samples
- NextSeq 500
Description
pancreas islet single-cell RNA-seq Overall design: isolated from 2 wt
Publication Title
Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 188 Downloadable Samples
- Illumina HiSeq 2500
Description
Background: The main bottleneck for genomic studies of tumors is the limited availability of fresh frozen (FF) samples collected from patients, coupled with comprehensive long-term clinical follow-up. This shortage could be alleviated by using existing large archives of routinely obtained and stored Formalin-Fixed Paraffin-Embedded (FFPE) tissues. However, since these samples are partially degraded, their RNA sequencing is technically challenging. Results: In an effort to establish a reliable and practical procedure, we compared three protocols for RNA sequencing using pairs of FF and FFPE samples, both taken from the same breast tumor. In contrast to previous studies, we compared the expression profiles obtained from the two matched sample types, using the same protocol for both. Three protocols were tested on low initial amounts of RNA, as little as 100 ng, to represent the possibly limited availability of clinical samples. For two of the three protocols tested, poly(A) selection (mRNA-seq) and ribosomal-depletion, the total gene expression profiles of matched FF and FFPE pairs were highly correlated. For both protocols, differential gene expression between two FFPE samples was in agreement with their matched FF samples. Notably, although expression levels of FFPE samples by mRNA-seq were mainly represented by the 3'-end of the transcript, they yielded very similar results to those obtained by ribosomal-depletion protocol, which produces uniform coverage across the transcript. Further, focusing on clinically relevant genes, we showed that the high correlation between expression levels persists at higher resolutions. Conclusions: Using the poly(A) protocol for FFPE exhibited, unexpectedly, similar efficiency to the ribosomal-depletion protocol, with the latter requiring much higher (2-3 fold) sequencing depth to compensate for the relative low fraction of reads mapped to the transcriptome. The results indicate that standard poly(A)-based RNA sequencing of archived FFPE samples is a reliable and cost-effective alternative for measuring mRNA-seq on FF samples. Expression profiling of FFPE samples by mRNA-seq can facilitate much needed extensive retrospective clinical genomic studies. Overall design: We perform an unbiased evaluation of RNA-seq of archived tumor tissues by comparing the same library preparation methods for both FF and FFPE matched tumor samples and for small amounts of total RNA starting material. We have 3 matched FF/FFPE tumor samples with a moderate archival time of about 4-5 years (T1=T3), and additional 3 FFPE tumor samples archived for more than 10 years (T4-T6). all samples were tested with two protocols: illumina Truseq RNA after poly(A) selection (mRNA-seq); and Truseq after ribosomal depletion (RiboZero). Several initial amounts of starting material was tested for eacg protocol.
Publication Title
mRNA-seq whole transcriptome profiling of fresh frozen versus archived fixed tissues.
Sample Metadata Fields
Specimen part, Disease, Subject
View Samples- Homo sapiens
- 14 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
IL-21 induces B cell activation, and differentiation into antibody-secreting plasmablasts in vitro. This process is abolished by loss-of function mutations in STAT3
Publication Title
IL-21 signalling via STAT3 primes human naive B cells to respond to IL-2 to enhance their differentiation into plasmablasts.
Sample Metadata Fields
Specimen part, Disease
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
- 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- 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