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SRP055671
Mus musculus
10 Downloadable Samples
Illumina HiSeq 2000
Description
Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome. Overall design: RNA-seq profile of developing distal limbs of mutants and WT animals at E11.5
Publication Title
Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 26 Downloadable Samples
- IlluminaHiSeq2000
Description
Inflammasomes are intracellular innate immune sensors that respond to pathogen and damage-associated signals with the proteolytic cleavage of caspase-1, resulting in IL-1_ and IL-18 secretion and macrophage pyroptosis. The discovery that heterozygous gain-of-function mutations in NLRP3 lead to oversecretion of IL-1_ and cause the autoinflammatory disease spectrum Cryopyrin Associated Periodic Syndrome (CAPS), led to the successful use of IL-1 blocking therapies1. We found that a de novo missense mutation in the regulatory domain of the NLRC4 (IPAF, CARD12) inflammasome causes early-onset recurrent fever flares and Macrophage Activation Syndrome (MAS). Functional analyses demonstrated spontaneous production of the inflammasome-dependent cytokines IL-1² and IL-18 exceeding levels in CAPS patients. The NLRC4 mutation led to constitutive caspase-1 cleavage in transduced cells and enhanced spontaneous production of IL-18 by both patient and NLRC4 mutant macrophages. Thus, we describe a novel monoallelic inflammasome defect that expands the autoinflammatory paradigm to include MAS and suggests novel targets for therapy. Overall design: Whole blood RNA-seq from seven timepoints of one patient with NLRC4-MAS as compared to five healthy pediatric controls, 7 NOMID patients with active disease prior to anakinra treatment and the same 7 NOMID patients with inactive disease after anakinra treatment. Please note that seven time points are chronologic time point. They are ordinal, in that "1" was drawn before "2", but the distance in time between points is not constant. Thus, time points 4 through 7 correspond to samples drawn while the patient was well AND on treatment. However there may be differences between 4 and 7 pertaining to the length of treatment, and for that reason any of these samples were not considered replicates.
Publication Title
An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 96 Downloadable Samples
Illumina HumanHT-12 V4.0 expression beadchip
Description
Basal airway epithelial cells (AEC) constitute stem/progenitor cells within the central airways and respond to mucosal injury in an ordered sequence of spreading, migration, proliferation, and dif-ferentiation to needed cell types. However, dynamic gene transcription in the early events after mucosal injury has not been studied in AEC. We examined gene expression using microarrays following mechanical injury (MI) in primary human AEC grown in submersion culture to generate basal cells and in the air-liquid interface to generate differentiated AEC (dAEC) that include goblet and ciliated cells. A select group of ~150 genes was in differential expression (DE) within 2 - 24 hr after MI, and enrichment analysis of these genes showed over-representation of functional categories related to inflammatory cytokines and chemokines. Network-based gene prioritization and network reconstruction using the PINTA heat kernel diffusion algorithm demonstrated highly connected networks that were richer in differentiated AEC compared to basal cells. Similar ex-periments done in basal AEC collected from asthmatic donor lungs demonstrated substantial changes in DE genes and functional categories related to inflammation compared to basal AEC from normal donors. In dAEC, similar but more modest differences were observed. We demon-strate that the AEC transcription signature after MI identifies genes and pathways that are im-portant to the initiation and perpetuation of airway mucosal inflammation. Gene expression oc-curs quickly after injury and is more profound in differentiated AEC, and is altered in AEC from asthmatic airways. Our data suggest that the early response to injury is substantially different in asthmatic airways, particularly in basal airway epithelial cells.
Publication Title
Chemokine expression in the early response to injury in human airway epithelial cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 19 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
An integrative analysis of this compendium of proteomic alterations and transcriptomic data was performed revealing only 48-64% concordance between protein and transcript levels. Importantly, differential proteomic alterations between metastatic and clinically localized prostate cancer that mapped concordantly to gene transcripts served as predictors of clinical outcome in prostate cancer as well as other solid tumors.
Publication Title
Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 58 Downloadable Samples
- IlluminaGenomeAnalyzerII, IlluminaGenomeAnalyzer
Description
Noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease and to reveal uncharacterized aspects of tumor biology. Here we discover 121 unannotated prostate cancer–associated ncRNA transcripts (PCATs) by ab initio assembly of high-throughput sequencing of polyA+ RNA (RNA-Seq) from a cohort of 102 prostate tissues and cells lines. We characterized one ncRNA, PCAT-1, as a prostate-specific regulator of cell proliferation and show that it is a target of the polycomb repressive complex 2 (PRC2). We further found that patterns of PCAT-1 and PRC2 expression stratified patient tissues into molecular subtypes distinguished by expression signatures of PCAT-1–repressed target genes. Taken together, our findings suggest that PCAT-1 is a transcriptional repressor implicated in a subset of prostate cancer patients. These findings establish the utility of RNA-Seq to identify disease-associated ncRNAs that may improve the stratification of cancer subtypes. Overall design: 21 prostate cell lines sequenced on the Illumina Genome Analyzer and GAII. Variable number of replicates per sample. RNA-Seq data from prostate cancer tissues used in this study will be made available on dbGAP.
Publication Title
Transcriptome sequencing across a prostate cancer cohort identifies PCAT-1, an unannotated lincRNA implicated in disease progression.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
To test whether vitamin D has a functionally important effect upon primary alveolar epithelial type II cells we used gene expression microarray to identify genes that are regulated by 25-dihydroxyvitamin D in adult alveolar type II cells.
Publication Title
Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS).
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples