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SRP151147
Homo sapiens
54 Downloadable Samples
Illumina HiSeq 2500
Description
Human lymphoid tissues harbor, in addition to CD56bright and CD56dim natural killer (NK) cells, a third NK cell population: CD69+CXCR6+ lymphoid tissue (lt)NK cells. The function and development of ltNK cells remain poorly understood. In this study we performed RNA sequencing on the CD56bright and CD56dim NK cells (from bone marrow and blood), and the ltNK cells (from bone marrow). In addition, the blood derived CD56dim, and bone marrow derived ltNK cells were further subdivided into a NKG2A+ and NKG2A- fraction. Paired blood and bone marrow samples of 4 healthy donors were included. When comparing the NKG2A fractions, only 3 genes (of 9382 genes included) had a significantly differential expression. Therefore, we pooled the expression data proportionally from the NKG2A+ and NKG2A- fractions in subsequent analyses. In ltNK cells, 1353 genes were differentially expressed compared to circulating NK cells. Several molecules involved in migration were downregulated in ltNK cells: S1PR1, SELPLG and CD62L. By flow cytometry we confirmed that the expression profile of adhesion molecules (CD49e-, CD29low, CD81high, CD62L-, CD11c-) and transcription factors (Eomeshigh, Tbetlow) of ltNK cells differed from their circulating counterparts. LtNK cells were characterized by enhanced expression of inhibitory receptors TIGIT and CD96 and low expression of DNAM1 and cytolytic molecules (GZMB, GZMH, GNLY). Their proliferative capacity was reduced compared to the circulating NK cells. By performing gene set enrichment analysis we identified DUSP6 and EGR2 as potential regulators of the ltNK cell transcriptome. Remarkably, comparison of the ltNK cell transcriptome to the published human spleen-resident memory CD8+ T (Trm) cell transcriptome revealed an overlapping gene signature. Moreover, the phenotypic profile of ltNK cells resembled that of CD8+ Trm cells in bone marrow. Together, we provide a comprehensive molecular framework of the conventional CD56bright and CD56dim NK cells as well as the tissue-resident ltNK cells and provide a core gene signature which might be involved in promoting tissue-residency. Overall design: mRNA sequencing of NK cell populations isolated from blood: CD56bright, NKG2A+ CD56dim and NKG2A- CD56dim, and bone marrow: CD56bright, CD56dim, NKG2A+ ltNK, and NKG2A- ltNK. Each sample has 4 biological replicates.
Publication Title
Human Bone Marrow-Resident Natural Killer Cells Have a Unique Transcriptional Profile and Resemble Resident Memory CD8<sup>+</sup> T Cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 16 Downloadable Samples
- NextSeq500
Description
Analysis of transcriptional differences between control and RA-treated cells during cardiac differentiation. The hypothesis tested in these samples is that addition of RA during differentiation towards atrial-like cardiomyocytes while control cells treated with DMSO result in ventricular-like cardiomyocytes. Overall design: NKX2.5 (eGFP/w)-hESCs were differentiated to cardiomyocytes with spin EB protocol, with the addition of RA or DMSO. Cells were sorted at day-31 based on GFP resulting in CTplus, CTminus, RAplus or RAminus goups. RNA was isolated from each of these fractions for sequencing.
Publication Title
KeyGenes, a Tool to Probe Tissue Differentiation Using a Human Fetal Transcriptional Atlas.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 298 Downloadable Samples
Affymetrix Human Exon 1.0 ST Array [transcript (gene) version, custom CDF (huex10st)
Description
Four different molecular classifications of muscle-invasive bladder cancer (MIBC) based on gene expression have been proposed. With the ultimate goal of utilizing these molecular subtypes for personalized treatment, we investigated their significance in the context of neoadjuvant cisplatin-based chemotherapy (NAC).
Publication Title
Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy.
Sample Metadata Fields
Age, Disease, Disease stage, Treatment
View Samples- Homo sapiens
- 20 Downloadable Samples
- IlluminaHiSeq2000
Description
Chromatin-based functional genomic analyses and genomewide association studies (GWASs) together implicate enhancers as critical elements influencing gene expression and risk for common diseases. Here, we performed systematic chromatin and transcriptome profiling in human pancreatic islets. Integrated analysis of islet data with those generated by the ENCODE project in nine cell types identified specific and significant enrichment of type 2 diabetes and related quantitative trait GWAS variants in islet enhancers. Our integrated chromatin maps reveal that most enhancers are short (median = 0.8 kb). Each cell type also contains a substantial number of more extended (=3 kb) enhancers. Interestingly, these stretch enhancers are often tissue-specific and overlap locus control regions, suggesting that they are important chromatin regulatory beacons. Indeed, we show that (i) tissue specificity of enhancers and nearby gene expression increase with enhancer length; (ii) neighborhoods containing stretch enhancers are enriched for important cell type-specific genes; and (iii) GWAS variants associated with traits relevant to a particular cell type are more enriched in stretch enhancers compared with short enhancers. Reporter constructs containing stretch enhancer sequences exhibited tissue-specific activity in cell culture experiments and in transgenic mice. These results suggest that stretch enhancers are critical chromatin elements for coordinating cell type-specific regulatory programs and that sequence variation in stretch enhancers affects risk of major common human diseases. Overall design: Integrated analysis of islet chromatin modification and transcriptome data with those generated by the ENCODE project. NISC Comparative Sequencing Program
Publication Title
Chromatin stretch enhancer states drive cell-specific gene regulation and harbor human disease risk variants.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 31 Downloadable Samples
- Illumina HiSeq 2500
Description
Large-scale genome sequencing is poised to provide a substantial increase in the rate of discovery of disease-associated mutations, but the functional interpretation of such mutations remains challenging. Here we show that deletions of a sequence on human chromosome 16 that we term the intestine-critical region (ICR) cause intractable congenital diarrhoea in infants. Reporter assays in transgenic mice show that the ICR contains a regulatory sequence that activates transcription during the development of the gastrointestinal system. Targeted deletion of the ICR in mice caused symptoms that recapitulated the human condition. Transcriptome analysis revealed that an unannotated open reading frame (Percc1) flanks the regulatory sequence, and the expression of this gene was lost in the developing gut of mice that lacked the ICR. Percc1 knockout mice displayed phenotypes similar to those observed on ICR deletion in mice and patients, whereas an ICR-driven Percc1 transgene was sufficient to rescue the phenotypes found in mice that lacked the ICR. Together, our results identify a gene that is critical for intestinal function and underscore the need for targeted in vivo studies to interpret the growing number of clinical genetic findings that do not affect known protein-coding genes. Overall design: Total RNA-seq from dissected regions of the digestive tract, from wild-type and percc1-/- mice.
Publication Title
Noncoding deletions reveal a gene that is critical for intestinal function.
Sample Metadata Fields
Specimen part, Subject
View Samples- Rattus norvegicus
- 75 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Demonstration of reduced biological effects with a prototypic modified risk tobacco product.
Publication Title
A 28-day rat inhalation study with an integrated molecular toxicology endpoint demonstrates reduced exposure effects for a prototypic modified risk tobacco product compared with conventional cigarettes.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Matrix metalloproteinase 7 (MMP7) is expressed at low levels in intact, normal airways by non-mucous-producing cells, including ciliated cells. In response to injury and infection, MMP7 expression is quickly and markedly upregulated and functions to regulate wound repair and various mucosal immune processes. We evaluated the global transcriptional response of airway epithelial cells from wild type and Mmp7-null mice cultured at an air-liquid interface. A common injury response was seen in both genotypes with up-regulation of genes associated with proliferation and migration. Analysis of differentially expressed genes between genotypes after injury revealed enrichment of functional categories associated with inflammation, cilia and differentiation. Because these analyses suggested MMP7 regulated ciliogenesis, we evaluated the recovery of the airway epithelium in wild type and Mmp7-null mice in vivo after naphthalene injury. These studies identified a new role for MMP7 in attenuating ciliogenesis during wound repair.
Publication Title
Matrix metalloproteinase-7 coordinates airway epithelial injury response and differentiation of ciliated cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 177 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Primitive neuroectodermal tumors of the central nervous system (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children. Using DNA methylation and gene expression profiling we have demonstrated that a significant proportion of institutionally diagnosed CNS PNETs display molecular profiles indistinguishable from those of various other well defined CNS tumor entities, facilitating diagnosis and appropiate therapy for children with these tumors. From the remaining fraction of CNS PNETs, we have identified four distinct new CNS tumor entities extending to other neuroepithelial tumors, each associated with a recurrent genetic alteration and particular histopathological and clinical features. These molecular entities, designated CNS Neuroblastoma with FOXR2 activation (CNS NB FOXR2), CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT CIC), CNS high grade neuroepithelial tumor with MN1 alteration (CNS HGNET MN1), and CNS high grade neuroepithelial tumor with BCOR alteration (CNS HGNET BCOR), will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by these poorly differentiated CNS tumors.
Publication Title
New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs.
Sample Metadata Fields
Sex, Age
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The cancer-risk associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long non-coding RNA CCAT2 in the highly amplified 8q24.21 region has been implicated in cancer predisposition, though causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by downregulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel disease-specific RNA mutation (named DNA-to-RNA allelic imbalance, DRAI) at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.
Publication Title
Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA <i>CCAT2</i> induce myeloid malignancies via unique SNP-specific RNA mutations.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 484 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples