RNA-seq was used to evaluate transcriptional changes in alloreactive TCR-Tg CD8 T cells during activation and tolerance induction. CBA mice were exposed to a low dose whole body irradiation and then injected with bone marrow from TCR-Tg KB5 mice to generate synchimeric mice. The KB5 TCR recognizes alloantigens from H2b MHC molecules, specifically Kb, that are expressed by C57BL/6 mice. The injection of bone marrow from KB5 mice into CBA mice enables the development of small and traceable population of TCR-Tg KB5 CD8 T cells. A clonotypic antibody specific for the KB5 TCR allows these cells to be monitored and sorted from the periphery of synchimeric mice by flow cytometry. KB5 CD8 T cells were purified by sorting cells from synchimeric mice under the following conditions: 1) not exposed to alloantigens and in a naïve state, 2) exposed to H2b antigens from C57BL/6 mice to activate the KB5 CD8 T cells, 3) exposed to H2b antigens in the presence of anti-CD154 that blocks costimulatory signals and induces transplantation tolerance, or 4) treated with alloantigens, anti-CD154 and LPS, that induces an inflammatory response and abrogates the induction of tolerance. KB5 CD8 T cells were FACS purified to a level of greater than 95%, RNA was recovered from the purified cells and RNA-seq was performed on triplicate samples from 3 independent experiments. Overall, the analyses revealed expression changes for a number of genes that regulate immune responses and inflammation, cell proliferation and immune cell homing. Overall design: Determine the changes in gene expression profiles that are induced during constimulation blockade.
Cutting Edge: Early Attrition of Memory T Cells during Inflammation and Costimulation Blockade Is Regulated Concurrently by Proapoptotic Proteins Fas and Bim.
Specimen part, Treatment, Subject
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LRH-1 governs vital transcriptional programs in endocrine-sensitive and -resistant breast cancer cells.
Specimen part, Cell line
View SamplesTumor characteristics are decisive in the determination of treatment strategy for breast cancer patients. Patients with estrogen receptor- (ER) positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the liver receptor homolog-1 (LRH-1, NR5A2) in anti-estrogen (AE) sensitive and resistant breast cancer cells. We identified genome-wide LRH-1 binding sites using ChIP-seq, uncovering preferential binding to regions distal to transcriptional start sites (TSS). We further characterized these LRH-1 binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1 binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1 depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in AE-sensitive and AE-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with signature of poor outcome breast cancer tumors in vivo. Herein report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies.
LRH-1 governs vital transcriptional programs in endocrine-sensitive and -resistant breast cancer cells.
Specimen part, Cell line
View SamplesBackground: Studies in mice have shown that PPAR is an important regulator of lipid metabolism in liver and a key transcription factor involved in the adaptive response to fasting. However, much less is known about the role of PPAR in human liver. Here we set out to study the function of PPAR in human liver via analysis of whole genome gene regulation in human liver slices treated with the PPAR agonist Wy14643.
The impact of PPARα activation on whole genome gene expression in human precision cut liver slices.
Sex, Specimen part, Treatment, Subject, Time
View SamplesLittle is known about the early transcriptional events in innate immune signaling in immature and tolerogenic monocyte-derived dendritic cells (DCs), the professional antigen-presenting cells of our immune system. TLR ligands usually induce a proinflammatory transcriptional response, whereas IL10 and/or dexamethasone induce a more tolerogenic phenotype.
MicroRNA genes preferentially expressed in dendritic cells contain sites for conserved transcription factor binding motifs in their promoters.
Specimen part
View SamplesSmall intestinal innate lymphoid cells (ILCs) are known to regulate intestinal epithelial cell homeostasis and to help prevent pathogenic bacterial infections, by producing IL-22. However, other functions of these cells and the lineal relationship between ILCs and lymphoid or myeloid cells have not been clear.
Intestinal Lin- c-Kit+ NKp46- CD4- population strongly produces IL-22 upon IL-1β stimulation.
Sex, Age, Specimen part
View SamplesGENES ASSOCIATED WITH THE CELL CYCLE, LINEAGE COMMITMENT AND IMMUNOMODULATORY POTENTIAL DISCRIMINATE HUMAN POSTNATAL STEM CELLS OF DIFFERENT ORIGIN.
Functional differences between mesenchymal stem cell populations are reflected by their transcriptome.
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View SamplesIn this study we aimed to identify a baseline intrahepatic transcriptional signature associated with response in chronic hepatitis B patients treated with peginterferon-alfa-2a (peg-IFN) and adefovir.
An intrahepatic transcriptional signature of enhanced immune activity predicts response to peginterferon in chronic hepatitis B.
Specimen part, Disease, Disease stage
View SamplesEthanol exposure during prenatal development causes fetal alcohol spectrum disorder (FASD), the most frequent preventable birth defect and neurodevelopmental disability syndrome. The molecular targets of ethanol toxicity during development are poorly understood. Developmental stages surrounding gastrulation are very sensitive to ethanol exposure. To understand the effects of ethanol on early transcripts during embryogenesis, we treated zebrafish embryos with ethanol during pre-gastrulation period and examined the transcripts by Affymetrix GeneChip microarray before gastrulation. We identified 521 significantly dysregulated genes, including 61 transcription factors in ethanol-exposed embryos. Sox2, the key regulator of pluripotency and early development was significantly reduced. Functional annotation analysis showed enrichment in transcription regulation, embryonic axes patterning, and signaling pathways, including Wnt, Notch and retinoic acid. We identified all potential genomic targets of 25 dysregulated transcription factors and compared their interactions with the ethanol-dysregulated genes. This analysis predicted that Sox2 targeted a large number of ethanol-dysregulated genes. A gene regulatory network analysis showed that many of the dysregulated genes are targeted by multiple transcription factors. Injection of sox2 mRNA partially rescued ethanol-induced gene expression, epiboly and gastrulation defects. Additional studies of this ethanol dysregulated network may identify therapeutic targets that coordinately regulate early development.
Embryonic ethanol exposure alters expression of sox2 and other early transcripts in zebrafish, producing gastrulation defects.
Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin.
Age, Specimen part, Cell line, Treatment, Time
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