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SRP137222
Mus musculus
12 Downloadable Samples
Illumina HiSeq 2000
Description
Hereditary sensory and autonomic neuropathy type I (HSAN-I) is neurological disorder characterized by distal sensory neuron dysfunction, frequent infections, and ulcerative mutilations. It remains unknown if HSAN-I directly dampens protective immunity. Here we report that HSAN-I-causing mutations of serine palmitoyltransferase long chain base subunit 2 (SPTLC2) affect human T cell responses. T cell antigenic stimulation and inflammation induce SPTLC2 expression. Murine T cell-specific ablation of Sptlc2 fundamentally impairs antiviral T cell survival and effector function. Mechanistically, SPTLC2-deficiency reduces sphingolipid biosynthetic flux and causes a prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress and CD8+ T cell death. Antiviral CD8+ T cell responses are restored by supplementing sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Our study reveals that SPTLC2 underpins protective adaptive immunity by translating extracellular stimuli into intracellular anabolic signals and reducing cellular stress to maintain metabolic reprogramming sustainability Overall design: Triplicates of each group were used for RNA-seq. Four groups were studied: Wild-type and SPTLC2-deficient CD8+ T cells, harvested from either naïve mice (D0) or mice infected with LCMV Armstrong 8 days earlier (D8).
Publication Title
Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8<sup>+</sup> T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.
Sample Metadata Fields
Treatment, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The role of FoxP3+ regulatory T (Treg) cells in the maintenance of immunological tolerance is well established. Recently, genome-wide association studies (GWAS) in humans have associated polymorphisms within the BACH2 locus encoding the transcription factor BTB and CNC homology 1, basic leucine zipper transcription factor 2 (Bach2) with diverse allergic and autoimmune diseases including asthma, multiple sclerosis, Crohn's disease, celiac disease, generalized vitiligo and type 1 diabetes. Common to these diseases is a failure to adequately maintain immunological tolerance. However, a role for Bach2 in this process has not been established.Here, by assessing the phenotype of mice in which the Bach2 gene is disrupted, we demonstrate a non-redundant role for Bach2 in the prevention of a spontaneous lethal inflammatory disorder predominantly affecting the lung and gut with excessive T helper 2 (Th2) responses and formation of circulating autoantibodies. Bach2 was necessary for efficient induction of FoxP3 expression both during thymopoesis and upon stimulation of nave peripheral CD4+ T cells under Treg polarizing conditions in vitro. Consequently, in bone marrow reconstitution experiments, Bach2 expression within the haematopoetic system was necessary for suppression of lethal autoimmunity in a manner that was FoxP3 dependent. These findings demonstrate a requirement for Bach2 in early lineage commitment of both thymic and induced Treg cells and point to shared mechanisms that underlie diverse allergic and autoimmune disorders that may serve as targets in the development of novel therapeutic strategies.
Publication Title
BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis.
Sample Metadata Fields
Sex, Specimen part
View Samples- Arabidopsis thaliana
- 16 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
Transcriptional profiling of an Fd-GOGAT1/GLU1 mutant in Arabidopsis thaliana reveals a multiple stress response and extensive reprogramming of the transcriptome
Publication Title
Transcriptional profiling of an Fd-GOGAT1/GLU1 mutant in Arabidopsis thaliana reveals a multiple stress response and extensive reprogramming of the transcriptome.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
4T1 mouse mammary carcinoma cells have an autocrine FGFR active loop leading to constitutive activation of downstream signaling pathways. We found that FGFR inhibitors have a strong effect on the proliferation and survival of these cells.
Publication Title
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
4T1 mouse mammary carcinoma cells have an autocrine FGFR active loop leading to constitutive activation of downstream signaling pathways. We found that FGFR inhibitors have a strong effect on 4T1 tumors in-vivo.
Publication Title
Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Transcription factor Runx3 regulates interleukin-15-dependent natural killer cell activation.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
NK cells are innate immune cells that recognize and kill foreign, virally-infected and tumor cells without the need for prior immunization. NK expansion following viral infection is IL-2 or IL-15-dependent.
Publication Title
Transcription factor Runx3 regulates interleukin-15-dependent natural killer cell activation.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 3 Downloadable Samples
- Illumina HiSeq 2000
Description
Although localized to the mineralized matrix of bone, osteocytes are able to respond to systemic factors such as the calciotropic hormones 1,25(OH)2D3 and PTH. In the present studies, we examine the transcriptomic response to PTH in an osteocyte cell model and found that this hormone regulated an extensive panel of genes. Surprisingly, PTH uniquely modulated two cohorts of genes, one that was expressed and associated with the osteoblast to osteocyte transition and the other a cohort that was expressed only in the mature osteocyte. Interestingly, PTH's effects were largely to oppose the expression of differentiation-related genes in the former cohort, while potentiating the expression of osteocyte-specific genes in the latter cohort. A comparison of the transcriptional effects of PTH with those obtained previously with 1,25(OH)2D3 revealed a subset of genes that was strongly overlapping. While 1,25(OH)2D3 potentiated the expression of osteocyte-specific genes similar to that seen with PTH, the overlap between the two hormones was more limited. Additional experiments identified the PKA-activated phospho-CREB (pCREB) cistrome, revealing that while many of the differentiation-related PTH regulated genes were apparent targets of a PKA-mediated signaling pathway, a reduction in pCREB binding at sites associated with osteocyte-specific PTH targets appeared to involve alternative PTH activation pathways. That pCREB binding activities positioned near important hormone-regulated gene cohorts were localized to control regions of genes was reinforced by the presence of epigenetic enhancer signatures exemplified by unique modifications at histones H3 and H4. These studies suggest that both PTH and 1,25(OH)2D3 may play important and perhaps cooperative roles in limiting osteocyte differentiation from its precursors while simultaneously exerting distinct roles in regulating mature osteocyte function. Our results provide new insight into transcription factor-associated mechanisms through which PTH and 1,25(OH)2D3 regulate a plethora of genes important to the osteoblast/osteocyte lineage. Overall design: Fully differentiated IDG-SW3 cells were treated in biological triplicate with 100nM PTH for 24 hours prior to mRNA isolation and sequencing. Vehicle treated samples were previously published in GSE54783: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1323967 http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1323968 http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1323969
Publication Title
The parathyroid hormone-regulated transcriptome in osteocytes: parallel actions with 1,25-dihydroxyvitamin D3 to oppose gene expression changes during differentiation and to promote mature cell function.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The Epidermal Growth Factor Receptor 2 (ERBB2 or HER2) is amplified and overexpressed in approximately 20% of invasive breast cancers and is associated with metastasis and poor prognosis. Here we describe the role of a constitutively active splice variant of HER2 (Delta-HER2) in human mammary epithelial cells. Overexpression of Delta-HER2 in human mammary cells decreased apoptosis and increased proliferation and expression of epithelial-to-mesenchymal markers. It also induced invasion in three-dimensional cultures and promoted tumorigenicity and metastasis in vivo. In contrast, similar overexpression of wild-type HER2 failed to evoke the same effects. Unbiased protein-tyrosine phosphorylation profiling revealed a significant increase in phosphorylation of several key signaling proteins upon Delta-HER2 expression, some of which not previously shown to belong to the HER2 pathway. In addition, microarray analysis revealed the expression of a set of genes specifically associated with Delta-HER2 expression. We found those genes to be highly expressed in ER-negative, high grade and metastatic primary breast tumors. Altogether, these results provide new insights into the function of a tumorigenic splice variant of HER2 and the signaling cascade deriving from its activity
Publication Title
Mammary tumor formation and metastasis evoked by a HER2 splice variant.
Sample Metadata Fields
Cell line
View Samples