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GSE2466
Homo sapiens
111 Downloadable Samples
Affymetrix Human Genome U95A Array (hgu95a)
Description
We used high density oligonucleotide arrays to identify molecular correlates of genetically and clinically distinct subgroups of B-cell chronic lymphocytic leukemia (B-CLL). Gene expression profiling was used to profile the five most frequent genomic aberrations, namely deletions affecting chromosome bands 13q14, 11q22-q23, 17p13 and 6q21, and gains of genomic material affecting chromosome band 12q13. A strikingly high degree of correlation between loss or gain of genomic material and the amount of transcripts from the affected regions leads to the hypothesis of gene dosage as a significant pathogenic factor. Furthermore, the influence of the immunoglobulin variable heavy chain (VH) mutation status was determined. A clear distinction in the expression profiles of unmutated and mutated VH samples exists, which can be discovered using unsupervised learning methods. However, when samples were separated by gender, this separation could only be detected in samples from male patients.
Publication Title
Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 86 Downloadable Samples
- Affymetrix Human Genome U95B Array (hgu95b)
Description
molecular profiles (HG-U95B,C,D,E) of biopsy skeletal muscle samples obtained from 10 normal individuals and 10 DMD patients
Publication Title
Gene expression profiling of Duchenne muscular dystrophy skeletal muscle.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 24 Downloadable Samples
- Affymetrix Human Genome U95A Array (hgu95a)
Description
Molecular profiles of dystophin-deficient patients and normal human skeletal muscles on Affymetrix HG-U95A arrays
Publication Title
Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Invasive extravillous trophoblasts (EVTs) of the human placenta are critically involved in successful pregnancy outcome since they remodel the uterine spiral arteries to increase blood flow and oxygen delivery to the placenta and the developing fetus. To gain more insights into their biological role different primary cell culture models are commonly utilised. However, access to early placental tissue may be limited and primary trophoblasts rapidly cease proliferation in vitro impairing genetic manipulation. Hence, trophoblastic cell lines have been widely used as surrogates to study EVT function. Although the cell lines share some molecular marker expression with their primary counterpart, it is unknown to what extent they recapture the invasive phenotype of EVT. Therefore, we here report the first thorough GeneChip analyses of SGHPL-5, HTR-8/SVneo, BeWo, JEG-3 and the novel ACH-3P trophoblast cells in comparison to previously analysed primary villous cytrophoblasts and extravillous trophoblasts.
Publication Title
Trophoblast invasion: assessment of cellular models using gene expression signatures.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional p38alpha alleles, we investigated its function in postnatal development and tumorigenesis. When p38alpha is specifically deleted in the mouse embryo, fetuses develop to term but die shortly after birth, likely due to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha display increased proliferation, resulting from sustained activation of the c-Jun N-terminal kinase (JNK)/c-Jun pathway. Importantly, in chemical-induced liver cancer development, mice with liver-specific deletion of p38alpha show enhanced hepatocyte proliferation and tumor development that also correlates with JNK/c-Jun upregulation. Furthermore, increased proliferation of p38alpha-deficient hepatocytes and tumor cells is suppressed by inactivation of JNK or c-Jun. These results reveal a novel mechanism whereby p38alpha negatively regulates cell proliferation through antagonizing the JNK/c-Jun pathway in multiple cell types and in liver cancer development.
Publication Title
p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 75 Downloadable Samples
NextSeq 500, Illumina HiSeq 2500
Description
IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that, under steady-state conditions, IL-7 signaling is principally mediated by activation of signal transducers and activators of transcription 5 (STAT5). In contrast, under lymphopenic conditions, there is a modulation of STAT1 expression resulting in an IL-7-dependent STAT1 and STAT5 activation. Consequently, the IL-7-induced transcriptome is altered with enrichment of IFN-stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4+ T cells undergoing lymphopenia-induced proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, "switching on" an alternate IL-7-dependent program. This mechanism could be a physiological process to regulate the expansion and size of the CD4+ T cell pool. During HIV infection, the virus could exploit this pathway, leading to the homeostatic dysregulation of the T cell pools observed in these patients. Overall design: Sorted naive CD4 T and CD8 T cells from WT or STAT1 transgenic mice were stimulated for 90 minutes with IL-7 or IFNg. Additonally CD4 T cells from WT or STAT1 trangenic or IL7Ra449F transgenic mice were stimulated for overnight with IL-7 or IFNg or IFNa4. Up to four biological replicates tested for each condition.
Publication Title
IL-7-dependent STAT1 activation limits homeostatic CD4+ T cell expansion.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 21 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Susceptibility genes for Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), monogenetic disorders with intellectual disabilities (ID) or schizophrenia (SCZ) converge on processes related to neuronal function and differentiation. Furthermore, ASD risk genes are enriched for FMRP (Fragile X Mental Retardation Protein) targets and for genes implicated in ID. In addition, a significant co-heritability was observed between ASD and SCZ. The genetic overlap between ASD, FXS, ID and SCZ together with the symptomatic differences gives rise to the question if pathomechanisms impair the same or different regulatory patterns activated during neuronal differentiation (ND). To test this idea, we performed transcriptome analysis of in-vitro differentiation of the neuroblastoma cell line model SH-SY5Y and identified genes that were differentially expressed, dynamically regulated, and coordinately expressed. The identified genetic modules activated during ND are enriched for genetic risk factors for these four disorders. Although risk genes for the disorders significantly overlap, we observed disorder specific enrichments: ASD or FXS implicated genes were likely to be positive regulators of ND whereas ID implicated genes were related to negative regulation. ASD and SCZ genes were specifically enriched among cholesterol and fatty acid associated modules. ID genes were overrepresented among cell cycle modules. In addition, we show that ASD genes are likely to be hub genes. We hypothesize that knowledge about genetic variants of an individual combined with network and pathway context of the related genes will allow differentiating between psychiatric disorders.
Publication Title
Transcriptomic signatures of neuronal differentiation and their association with risk genes for autism spectrum and related neuropsychiatric disorders.
Sample Metadata Fields
Sex, Specimen part, Cell line
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The non-coding Xist RNA triggers silencing of one of the two female X chromosomes during X inactivation in mammals. Gene silencing by Xist is restricted to special developmental contexts found in cells of the early embryo and specific hematopoietic precursors. The absence of critical silencing factors might explain why Xist cannot silence outside these contexts. Here, we show that Xist can also initiate silencing in a lymphoma model. Using the tumor context we identify the special AT rich binding protein SATB1 as an essential silencing factor. We show that loss of SATB1 in tumor cells abrogates the silencing function of Xist. In normal female lymphocytes Xist localizes along SATB1 filaments and, importantly, forced Xist expression can relocalize SATB1 into the Xist cluster. This reciprocal influence on localization suggests a molecular interaction between Xist and SATB1. SATB1 and its close homologue SATB2 are expressed during the initiation window for X inactivation in embryonic stem cells and are recruited to surround the Xist cluster. Furthermore, ectopic expression SATB1 or SATB2 enables gene silencing by Xist in embryonic fibroblasts, which normally do not provide an initiation context. Thus, SATB1 functions as a crucial initiation factor and may act to organize genes for silencing by Xist during the initiation of X inactivation.
Publication Title
SATB1 defines the developmental context for gene silencing by Xist in lymphoma and embryonic cells.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 29 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
In psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell-derived cytokines. Evidence now suggests that Th17 and Th22 cells infiltrate psoriasis lesions and by secreting IL-17 and IL-22, respectively, may drive disease-specific gene or cell responses. While studies in model systems indicate that IL-22 has a dominant pathogenic role, there is evolving evidence that IL-17 contributes to features of psoriasis. To more fully understand the role of IL-17 in human disease pathogenesis, we examined psoriatic skin lesions obtained from patients treated with an anti-IL-17 (IL-17 A) monoclonal antibody, LY2439821. In a phase 1, randomized, double-blind, placebo-controlled dose escalation trial, patients with chronic psoriasis were randomized to receive 3 doses of subcutaneous LY2439821 at 5 mg (n=8), 15 mg (n=8), 50 mg (n=8), 150 mg (n=8) or placebo (n=8) at weeks 0, 2 and 4. Repeat biopsies were taken from the same lesional area at baseline, week 2 and 6. At week 6, a PASI75 was observed in 0/8, 2/8, 5/7 and 8/8 patients receiving 5 mg, 15 mg, 50 mg or 150 mg LY2439821 respectively and 0/8 patients receiving placebo. The antibody was well-tolerated. In patients receiving the two highest doses, histological and immunohistochemical analyses of biopsies revealed significant reductions from baseline in keratinocyte proliferation, hyperplasia and epidermal thickness after 2 weeks, as well as reduced infiltration into the dermis and epidermis by T-cells (CD3+) and dendritic cells (CD11c and DC-LAMP). Keratinocyte expression of innate defense proteins, S100A7, S100A8, beta-defensin2 and LL37/cathelicidin was also reduced. By week 6, the skin appeared normal with a reversal of disease defining pathological features. Quantitative RT-PCR revealed decreased expression of interferon gamma (IFN-gamma), IL-22 and IL-17, key cytokines from T cell subsets Th1, Th22 and Th17, respectively. In order to explore the extent to which IL-17 blockade influences an even broader set of inflammatory or psoriatic disease related genes, mRNA levels from skin biopsy samples were evaluated using whole genome microarrays. At week 2, the highest dose of LY2439821 modulated over 1500 genes significantly (>1.5 fold change [FC], p<0.05). Of these, 51 genes were strongly suppressed (>7-fold) including IL-19, lipocalin, amphiregulin, granzyme B, and several chemokines. In a separate analysis, those genes known to be synergistically regulated by both IL-17 and TNF-alpha showed the greatest normalization in expression compared to genes known to be regulated by TNF-alpha alone, IFN-gamma or Interferon alpha. Our data suggest that Th17 cells, through the expression of IL-17, mediate psoriasis pathogenesis, and that neutralization of IL-17 with LY2439821 suppresses signaling through multiple inflammatory circuits by inhibiting expression of cytokines from multiple T cell subsets, as well as chemokines, and antimicrobial proteins from keratinocytes.
Publication Title
IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis.
Sample Metadata Fields
Subject, Time
View Samples- Homo sapiens
- 11 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Invasion of cytotrophoblasts into uterine tissues is essential for placental development. To identify molecules regulating trophoblast invasion, mRNA signatures of purified villous (CTB, poor invasiveness) and extravillous (EVT, high invasiveness) trophoblasts isolated from first trimester human placentae and villous explant cultures, respectively, were compared using GeneChip analyses yielding 991 invasion/migration related transcripts. Several genes involved in physiological and pathologic cell invasion, including ADAM-12,-19,-28 as well as Spondin-2, were upregulated in EVT. Pathway prediction analyses identified several functional modules associated with either the invasive or the non-invasive trophoblast phenotype. One of the genes which were downregulated in the invasive mRNA pool, heme oxygenase-1 (HO-1), was selected for functional analyses. Real-time PCR analyses, Western blottting, and immunofluorescene of first trimester placentae and differentiating villous explant cultures demonstrated downregulation of HO-1 in invasive EVT as compared to CTB. Modulation of HO-1 expression in loss-of as well as gain-of function cell models (BeWo and HTR8/SVneo, respectively) demonstrated an inverse relationship of HO-1 expression with trophoblast migration in transwell and wound healing assays. Importantly, HO-1 expression led to an increase in protein levels and activity of the nuclear hormone receptor PPARgamma. Pharmacological inhibition of PPARgamma abrogated the inhibitory effects of HO-1 on trophoblast migration. Collectively, our results demonstrate that gene expression profiling of EVT and CTB can be used to unravel novel regulators of cell invasion. Accordingly, we identify heme oxygenase-1 as a negative regulator of trophoblast motility acting via upregulation of PPARgamma.
Publication Title
Identification of novel trophoblast invasion-related genes: heme oxygenase-1 controls motility via peroxisome proliferator-activated receptor gamma.
Sample Metadata Fields
No sample metadata fields
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