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SRP185829
Mus musculus
48 Downloadable Samples
Illumina HiSeq 2500
Description
Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 hours after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both, and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv vs. Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection, as GVHD severity was similar in recipients of wild-type Tconv combined with Notch-deprived vs. wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4+ Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and T helper polarization. In contrast, Notch inhibition dampened IFN-? and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with pathogenic effects of Notch in T cells at the earliest stages of GVHD. Overall design: 4 samples per cohort (Notch blockade using Dll1/4 neutralizing antibodies vs isotype control antibodies - GD) were analyzed. Additional 4 samples contained 4C T cells retrieved from syngeneic recipients.
Publication Title
Early Notch Signals Induce a Pathogenic Molecular Signature during Priming of Alloantigen-Specific Conventional CD4<sup>+</sup> T Cells in Graft-versus-Host Disease.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus, Homo sapiens
- 252 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302), Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integrating factor analysis and a transgenic mouse model to reveal a peripheral blood predictor of breast tumors.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 162 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We analyzed gene expression in human peripheral blood mononuclear cells (PBMCs) from breast cancer patients, patients with benign breast abnormalities, healthy cancer-free individuals as well as patients with other types of cancer (gastrointestinal and brain cancers).
Publication Title
Integrating factor analysis and a transgenic mouse model to reveal a peripheral blood predictor of breast tumors.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 90 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2), Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Female MMTV/c-MYC transgenic mice expressed the c-MYC proto-oncogene or a more stable point mutation variant (T58A) of the gene under the control of the hormone-responsive MMTV long terminal repeat (LTR) in an FVB/NJ background (Jackson Laboratories, Bar Harbor, ME). The hormones released during pregnancy and lactation have been shown to enhance expression of the oncogene. Thus, the mice were maintained in a continuous breeding program. Mice were monitored twice weekly for tumor development by palpation and tumors were measured twice weekly. Once the tumors reached 3cm3 the animals were sacrificed and tissue was obtained to confirm the tumors by histological analysis. As a control, female mice of the same age and background strain were maintained in the same facility and under the same breeding conditions as their transgenic counterparts.
Publication Title
Integrating factor analysis and a transgenic mouse model to reveal a peripheral blood predictor of breast tumors.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
In rodents, the uterus of a mature
Publication Title
Fine temporal analysis of DHT transcriptional modulation of the ATM/Gadd45g signaling pathways in the mouse uterus.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
17-Estradiol (E2) is well known to be associated with uterine cancer, endometriosis, and leiomyomas. Although insulin-like growth factor I (IGF-I) has been identified as a mediator of the uterotrophic effect of E2 in several studies, this mechanism is still not well understood. In the present study, identification of the genes modulated by a physiological dose of E2, in the uterus, has been done in ovariectomized mice using Affymetrix microarrays. The E2-induced genomic profile shows that multiple genes belonging to the IGF-I pathway are affected after exposure to E2. Two phases of regulation could be identified. First, from 0 to 6 h, the expression of genes involved in the cell cycle, growth factors, protein tyrosine phosphatases, and MAPK phosphatases is quickly upregulated by E2, while IGF-I receptor and several genes of the MAPK and phosphatidylinositol 3-kinase pathways are downregulated. Later, i.e., from 6 to 24 h, transporters and peptidases/proteases are stimulated, whereas defense-related genes are differentially regulated by E2. Finally, cytoarchitectural genes are modulated later. The present data show that a physiological dose of E2 induces, within 24 h, a series of transcriptional events that promote the uterotrophic effect. Among these, the E2-mediated activation of the IGF-I pathway seems to play a pivotal role in the uterotrophic effect. Furthermore, the protein tyrosine phosphatases and MAPK phosphatases are likely to modulate the estrogenic uterotrophic action by targeting, at different steps, the IGF-I pathway.
Publication Title
Temporal analysis of E2 transcriptional induction of PTP and MKP and downregulation of IGF-I pathway key components in the mouse uterus.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The efficacy and exceptionally good tolerance of estrogen blockade in the treatment of breast cancer is well recognized but novel agents are required, especially to take advantage of the multiple consecutive responses obtained in breast cancer progressing following previous hormone therapy, thus delaying the use of cytotoxic chemotherapy with its usually serious side effects. Acolbifene (ACOL) is a novel and unique antiestrogen completely free of estrogen-like activity in both the mammary gland and uterus while preventing bone loss. From the preclinical and clinical data so-far available, this new antiestrogen represents a unique opportunity for a highly potent and specific blockade of estrogen action in the mammary gland and uterus while exerting estrogen-like beneficial effects in other tissues (selective estrogen receptor modulator or SERM activity). In order to better understand the specificity of action of acolbifene, we have used Affymetrix GeneChips containing 45,000 probe sets to analyze 34,000 genes to determine the specificity of this compound compared to the pure antiestrogen fulvestrant, as well as the mixed antagonists/agonists tamoxifen and raloxifene to block the effect of estradiol (E2) and to induce effects of their own on gene expression in the mouse mammary gland. The genes modulated by E2 were those identified in two separate experiments and validated by quantitative real-time PCR (Q_RT-PCR). Three hours after the single subcutaneous injection of E2 (0.05 ug), the simultaneous administration of acolbifene, fulvestrant, tamoxifen and raloxifene blocked by 98%, 62%, 43% and 92% the number of E2-upregulated genes, respectively. On the other hand, 70%, 10%, 25% and 55% of the genes down-regulated by E2 were blocked by the same compounds. Acolbifene was also the compound which, when used alone, modulated the smallest number of genes also influenced by E2, namely 4%, thus possibly explaining the potent tumoricidal action of this compound in human breast cancer xenografts where 61% of tumors disappeared, thus bringing a new paradigm in the hormonal therapy of breast cancer.
Publication Title
Specific transcriptional response of four blockers of estrogen receptors on estradiol-modulated genes in the mouse mammary gland.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
Androgens have been postulated to be important modulators of adipose tissue metabolism and fat cell function. In the present study, we investigated the response of male and female mice retroperitoneal adipose tissue to the non-aromatizable androgen dihydrotestosterone (DHT). Adipose tissue samples were obtained in gonadectomized (GDX) animals treated with vehicle (control group), or injected with 0.1mg DHT at 1, 3, 6, 12, 18 and 24h prior to necropsy. Transcripts which were significantly modulated were considered as androgen-responsive genes. Quantitative real-time RT-PCR was used to confirm results from the microarry analysis in a subset of 46 probe sets in male mice and 98 probe sets in female mice. Using both methods and considering peak time versus control, 74.5% and 61.2% of the modulated genes were confirmed by PCR in males and females, respectively. Four genes were significantly stimulated in a similar manner by DHT in both sexes, namely metallothionein 1 (Mt1), growth arrest and DNA-damage-inducible 45 gamma (Gadd45g), cyclin-dependent kinase inhibitor 1A (Cdkn1a), and fk506-binding protein 5 (Fkbp5). All these genes appear to be associated with a down-regulation of adipocyte differentiation/proliferation and adipogenesis. In conclusion, this study which evaluated the transcriptome response of adipose tissue to DHT in male and female mice suggests that DHT consistently modulates genes involved in the regulation of adipogenesis in retroperitoneal adipose tissue of both male and female animals.
Publication Title
Response of the adipose tissue transcriptome to dihydrotestosterone in mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Androgen-induced bZIP (AIbZIP) is a basic leucine zipper (bZIP)
Publication Title
Transcriptional profiling of genes that are regulated by the endoplasmic reticulum-bound transcription factor AIbZIP/CREB3L4 in prostate cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 32 Downloadable Samples
- NextSeq 500
Description
We fine-mapped DNA methylation in neuronal nuclei (NeuN+) isolated by flow cytometry from post-mortem frontal cortex of the brain of individuals diagnosed with schizophrenia, bipolar disorder, and controls (n=29, 26, and 28 individuals). Overall design: Brain tissue samples (n=34 human samples, 17 case and 17 control) were lysed using QIAzol Lysis Reagent (Qiagen) and homogenized with a TissueLyser (Qiagen). Total RNA from each sample was isolated using the RNeasy Plus Universal Mini kit (Qiagen) according to manufacturer's instructions and included an enzymatic DNase (Qiagen) digestion step. RNA quality was measured on a 2100 Bioanalyzer (Agilent) and quantity was determined with a Nanodrop 2000 spectrophotometer (Thermo Fisher Scientific). Only RNA samples with a RIN quality score >7 proceeded to RNA-seq library preparation (RIN between 7.1 to 9.4 for all samples). Libraries were prepared by the Van Andel Genomics Core from 300 ng of total RNA using the KAPA RNA HyperPrep Kit with RiboseErase (v1.16) (Kapa Biosystems). RNA was sheared to 300-400 bp. Prior to PCR amplification, cDNA fragments were ligated to Bio Scientific NEXTflex Adapters (Bioo Scientific). Quality and quantity of the finished libraries were assessed using a combination of Agilent DNA High Sensitivity chip (Agilent Technologies, Inc.), QuantiFluor® dsDNA System (Promega Corp.), and Kapa Illumina Library Quantification qPCR assays (Kapa Biosystems). Individually indexed libraries were pooled, and 75 bp paired-end sequencing was performed on an Illumina NextSeq 500 sequencer, with all libraries run across 3 flowcells. Base calling was done by Illumina NextSeq Control Software (NCS) v2.0 and output of NCS was demultiplexed and converted to FastQ format with Illumina Bcl2fastq v1.9.0. Trimgalore (v0.11.5) was used for adapter removal prior to genome alignment. STAR33 (v2.3.5a) index was generated using Ensemble GRCh38 p10 primary assembly genome and the Gencode v26 primary assembly annotation. Read alignment was performed using a STAR two-pass mode. Gene counts matrix was imported into R (3.4.1) and low expressed genes (counts per million (CPM) < 1 in all samples) were removed prior to differential expression in EdgeR. Gene counts were normalized using the trimmed mean of M-values, fitted in a generalized linear model and differentially tested using a likelihood ratio test. The generalized linear model contained covariates age, sex, post mortem interval and neuronal cell composition. Cell-type compositions for each sample was accessed using CIBERSORT34 on normalized sample counts against cell-type specific markers, identifying the proportion of neurons in each samples. Benjamini Hochberg correction was used to adjust for multiple testing.
Publication Title
Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis.
Sample Metadata Fields
Sex, Age, Race, Subject
View Samples