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Mus musculus
8 Downloadable Samples
Illumina HiSeq 2000
Description
The underlying relation between Parkinson disease (PD) etiopathology and its major risk factor, aging, is largely unknown. The nature of the specific age-related mechanisms promoting PD onset is experimentally difficult to elucidate because aging is a highly complex process contributed by multiple factors. Recent evidence, however, established a strong and causative link between genome stability and aging. To investigate a possible nexus between DNA damage accumulation, aging, and PD we examined DNA repair pathways associated with aging in laboratory animal models and human cases. We demonstrate that dermal fibroblasts from PD patients display flawed nucleotide excision repair (NER) capacity and that NER-defective mice exhibit typical PD-like pathological alterations, including decreased dopaminergic innervation in the striatum, increased phospho-synuclein levels, and defects in mitochondrial respiration. NER mouse mutants are also more sensitive to the prototypical PD toxin MPTP and their transcriptomic landscape shares important similarities with that of PD patients. Overall, our results demonstrate that specific defects in DNA repair impact the dopaminergic system, are associated with human PD pathology, and might therefore constitute a novel risk factor for PD by affecting the aging process. Overall design: In total 8 samples were analyzed, 4 controls and 4 Ercc1 mutants.
Publication Title
Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
Sp1 and Sp3 belong to the Specificity proteins (Sp)/Krüppel-like transcription factor family. They are closely related, ubiquitously expressed and recognize G-rich DNA motifs. They are thought to regulate generic processes such as cell cycle and growth control, metabolic pathways and apoptosis. Ablation of Sp1 or Sp3 in mice is lethal, and combined haploinsufficiency results in hematopoietic defects during the fetal stages. Here, we show that in adult mice conditional ablation of either Sp1 or Sp3 has minimal impact on hematopoiesis, while the simultaneous loss of Sp1 and Sp3 results in severe macrothrombocytopenia and platelet dysfunction. We employed flow cytometry, cell culture and electron microscopy and show that although megakaryocyte numbers are normal in bone marrow and spleen, they display a less compact demarcation membrane system and a striking inability to form proplatelets. Through megakaryocyte transcriptomics and platelet proteomics we identified several cytoskeleton-related proteins and downstream effector kinases, including Mylk, that were downregulated upon Sp1/Sp3 depletion, providing an explanation for the observed defects in megakaryopoiesis. We show that Mylk is required for proplatelet formation and stabilization and for ITAM-receptor mediated platelet aggregation. Our data highlights the specific vs generic role of these ubiquitous transcription factors in the highly specialized megakaryocytic lineage. Overall design: Megakaryocyte mRNA profiles of Sp1fl/fl::Sp3fl/fl (WTlox) and Pf4-Cre::Sp1fl/fl::Sp3fl/fl (dKO) mice were generated by deep sequencing, in triplicate.
Publication Title
Sp1/Sp3 transcription factors regulate hallmarks of megakaryocyte maturation and platelet formation and function.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 11 Downloadable Samples
Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Genome wide mRNA and miRNA profiling was performed in SH-SY5Y cells stably overexpressing wild type or mutant MIR204 or MIR618. Mutants came from a large scale genetic screening of brain expressed miRNA genes in patients with schizophrenia or idiopathic generalized epilepsy and in control individuals. Based on enrichment of the variants with the schizophrenic or epileptic phenotype and based on impact prediction, two variants, one near MIR204 (rs7861254) and one in MIR618 (rs2682818) were selected for functional validation. Genome wide profiling of mRNA (micro-array) and mature miRNAs (small RNA sequencing, submitted to SRA) was performed in the created stable cells to assess the effect of the variants and to investigate the function of these miRNA genes.
Publication Title
Schizophrenia-Associated MIR204 Regulates Noncoding RNAs and Affects Neurotransmitter and Ion Channel Gene Sets.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
The accumulation of irreparable cellular damage restricts healthy lifespan after acute stress or natural aging. Senescent cells are thought to impair tissue function and their genetic clearance can successfully delay features of aging. Identifying how senescent cells avoid apoptosis would allow for the prospective design of anti-senescence compounds to address whether homeostasis can be restored. Here, we identify FOXO4 as a pivot in the maintenance of senescent cell viability. We designed a FOXO4-based peptide which selectively competes for interaction of FOXO4 with p53. In senescent cells, this results in p53 nuclear exclusion and cell-intrinsic apoptosis. Importantly, under conditions where it was well tolerated, the FOXO4 peptide restored liver function after Doxorubicin-induced chemotoxicity. Moreover, in fast aging XpdTTD/TTD, as well as in naturally aged mice the FOXO4 peptide could counteract the loss of fitness, fur density and renal function. Thus, it is possible to therapeutically target senescent cells and thereby effectively counteract senescence-associated loss of tissue homeostasis. Overall design: mRNA expression levels are compared between IR-induced senescent and proliferating IMR90 cells in triplicate
Publication Title
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 99 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. We demonstrate the existence of 3 molecular subtypes in a cohort of 99 cases and an independent cohort of 82 LMS. Two new FFPE tissue-compatible diagnostic immunohistochemical markers are identified: LMOD1 for subtype I LMS and ARL4C for subtype II LMS. Subtype I and subtype II LMS are associated with good and poor prognosis, respectively. The LMS subtypes show significant differences in expression levels for genes for which novel targeted therapies are being developed. Overall design: Gene expression profiling was performed by 3'' End RNA Sequencing (3SEQ), a next generation sequencing approach that does not rely on frozen tissue but can be performed on archival FFPE tissue. Samples included 99 LMS, 6 Undifferentiated Pleomorphic Sarcomas (UPS), 3 leiomyomas, 4 normal myometrium samples, and 1 case of Lymphangioleiomyomatosis (LAM). This study only includes the 99 LMS Samples. After gene expression levels were quantified by 3SEQ analysis pipeline, Consensus Clustering with bootstrap method was used to determine that the dataset contained three robust subtypes, and Silhouette analysis was performed to validate the subtype assignments. Two class SAM analysis (Significance Analysis of Microarrays) was performed to identify genes expressed differentially between each subtype of LMS with FDR of 0.05. Immunohistochemical staining was used to validate the potential diagnostic and prognostic markers from 3SEQ data on a tissue microarray.
Publication Title
Molecular subtyping of leiomyosarcoma with 3' end RNA sequencing.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
The vascular endothelium forms a physical barrier between blood and the surrounding tissue. Its constant exposure to haemodynamic shear stress controls endothelial barrier function which is of major importance for vascular homeostasis. The role of long non-coding RNAs (lncRNAs) in this process remains elusive. Here we identify the shear stress-induced lncRNA LASSIE (linc00520) as a stabilizer of adherens junctions (AJs) in endothelial cells (ECs), that is indispensable for normal endothelial barrier function and shear stress sensing. Silencing of LASSIE in ECs resulted in impaired cell survival, loss of cell-cell contacts and failure to align in the direction of flow. RNA affinity purification followed by mass spectrometry identified several junction proteins associated with LASSIE, including the endothelial adhesion protein PECAM-1 and intermediate filament (IF) protein nestin. Proteomic analysis of VE-cadherin-associated proteins showed that LASSIE silencing reduces VE-cadherin interaction with nestin and microtubule (MT)-associated cytoskeletal proteins. We confirmed that LASSIE silencing results in a decreased connection between VE-Cadherin and the cytoskeleton, resulting in loss of barrier function and shear stress sensing. Together, this study identifies the shear stress-induced lncRNA LASSIE as a critical link between AJs and the IF cytoskeleton, which is indispensable for normal EC junction stabilization and shear stress sensing.
Publication Title
Long non-coding RNA LASSIE regulates shear stress sensing and endothelial barrier function.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 53 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Purpose: Multiple studies from last decades have shown that the microenvironment of carcinomas plays an important role in the initiation, progression and metastasis of cancer. Our group has previously identified novel cancer stroma gene expression signatures associated with outcome differences in breast cancer by gene expression profiling of two tumors of fibroblasts as surrogates for physiologic stromal expression patterns. The aim of this study is to find additional new types of tumor stroma gene expression patterns. Results: 53 tumors were sequenced by 3SEQ with an average of 29 million reads per sample. Both the elastofibroma (EF) and fibroma of tendon sheath (FOTS) gene signatures demonstrated robust outcome results for survival in the four breast cancer datasets. The EF signature positive breast cancers (20-33% of the cohort) demonstrated significantly better outcome for survival. In contrast, the FOTS signature positive breast cancers (11-35% of the cohort) had a worse outcome. The combined stromal signatures of EF, FOTS, and our previously identified DTF, and CSF1 signatures characterize, in part, the stromal expression profile for the tumor microenvironment for between 74%-90% of all breast cancers. Conclusions: We defined and validated two new stromal signatures in breast cancer (EF and FOTS), which are significantly associated with prognosis. Overall design: Gene expression profiling by 3SEQ was performed on 8 additional types of fibrous tumors, to identify different fibrous tumor specific gene expression signatures. We then determined the significance of the fibrous tumor gene signatures in four publically available breast cancer datasets (GSE1456, GSE4922, GSE3494, NKI Dataset).
Publication Title
Next generation sequencing-based expression profiling identifies signatures from benign stromal proliferations that define stromal components of breast cancer.
Sample Metadata Fields
Specimen part, Subject
View Samples
SRP015977- Mus musculus
- 32 Downloadable Samples
- Illumina HiSeq 2000
Description
Profile gene expression from tumors that develop in mice bearing conditional activation of EWS-ATF1, compared to control mouse tissues from the chest wall as well as tumor samples from mouse models of synovial sarcoma and osteosarcoma achieved by conditional disruption of Rb1 and p53 Overall design: 13 clear cell sarcomas (5 started with Rosa26CreER, 4 with TATCre, 2 with Prx1CreERT2, and 2 with Bmi1IRESCreERT2), 7 osteosarcomas, 6 synovial sarcomas, 6 control samples
Publication Title
Modeling clear cell sarcomagenesis in the mouse: cell of origin differentiation state impacts tumor characteristics.
Sample Metadata Fields
Specimen part, Subject
View Samples- Drosophila melanogaster
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
The aim of the study was to generate transcriptome of wild-type and G9a mutant adult flies (females) 24h post-infection with Drosophila C Virus (DCV). Overall design: We generated 8 different data sets. For wild-type controls and G9a mutants, we performed both mock and DCV infection, and collected both whole flies and fat bodies. All flies were 3-5 days old females.
Publication Title
The epigenetic regulator G9a mediates tolerance to RNA virus infection in Drosophila.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Drosophila melanogaster
- 6 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
We infected Drosophila S2 cells (invitrogen) with Drosophila C virus (DCV) (Multiplicity of Infection = 10), and harvested samples for further analysis at 8 and 24 hours post-infection.
Publication Title
The heat shock response restricts virus infection in Drosophila.
Sample Metadata Fields
Cell line, Time
View Samples