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GSE103899
Mus musculus
24 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
We demonstrate that PKA signalling drives zonal conversion within adult adrenocortical lineage in a sexually dimorphic manner. Our data establish that Prkar1a genetic ablation (leading to constitutive PKA activation) in the adult adrenocortical lineage leads to endocrine hyperactivity and accelerates adrenal cortex renewal. This results in increased zona fasciculata differentiation and final conversion into reticularis-like zone. This phenomenon relies partly on sex-dependent mechanisms of cortical renewal, on which the male androgenic milieu exerts a repressive action through induction of WNT signalling, which in turn antagonizes PKA signalling and cortical cell turnover.
Publication Title
PKA signaling drives reticularis differentiation and sexually dimorphic adrenal cortex renewal.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 3 Downloadable Samples
Illumina HiSeq 2000
Description
Purpose: In all vertebrates, the thymus is necessary and sufficient for production of classic adaptive T cells. The key components of the thymus are cortical and medullary thymic epithelial cells (cTECs and mTECs). Despite the capital role of TECs, our understanding of TEC biology is quite rudimentary. For instance, we ignore what might be the extent of divergence in the functional program of these two TECs populations. It also remains unclear why the number of TECs decreases rapidly with age, thereby leading to progressive thymic insufficiency. Methods: Systems level understanding of cell function begins with gene expression profiling, and the transcriptome is currently the only ''-ome'' that can be reliably tackled in its entirety in freshly harvested primary cells. In order to gain novel insights into TEC biology, we therefore decided to analyse the whole transcriptome of cTECs, mTECs and skin epithelial cells. We elected to analyse gene expression using RNA-seq rather microarrays because RNA-seq has higher sensitivity and dynamic range coupled to lower technical variations. Results: Our deep sequencing approach provides a unique perspective into the transcriptome of TECs. Consistent with their ability to express ectopic genes, we found that mTECs expressed more genes than other cell populations. Out of a total of 15,069 genes expressed in TECs, 25% were differentially expressed by at least 5-fold in cTECs vs. mTECs. Genes expressed at higher levels in cTECs than mTECs regulate numerous cell functions including cell differentiation, cell movement and microtubule dynamics. Almost all positive regulators of the cell cycle were overexpressed in skin ECs relative to TECs. Conclusions: Our RNA-seq data provide novel insights into the transcriptional landscape of TECs, highlight substantial divergences in the transcriptome of TEC subsets and suggest that cell cycle progression is differentially regulated in TECS and skinECs. We believe that our work will therefore represent a valuable resource and will be of great interest to readers working in biological sciences, particularly in the areas of immunology and systems biology. Overall design: The mRNA profiles of cTEC, mTEC (from 14 thymi of 7-days old C57BL/6 mice) and skinEC (from the trunk and dorsum of seven newborn mice) were generated by RNA-sequencing using Illumina HiSeq2000.
Publication Title
Transcriptome sequencing of neonatal thymic epithelial cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 24 Downloadable Samples
- NextSeq 500
Description
BRAF oncogene is mutated in ~50% of human cutaneous melanomas. The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway fuelling cancer growth. The inhibitors of BRAF V600E (BRAFi), lead to massive and high response rate. However, BRAFi-resistant cells that operate as a cellular reservoir for relapses severely limits the duration of the clinical response. The recent depiction of these resistant cells did not identify druggable targets to ensure long-term survival under BRAFi. Here, we identify the aryl hydrocarbon receptor (AhR) as a target to eradicate resistant cells. We show that BRAFi bind to AhR on a new site, named beta-pocket, and reprogram gene expression independently of its partner ARNT. beta-pocket activation induces a pigmentation signature, which is associated to BRAFi-induced cell death of sensitive BRAF V600E melanoma cells and tumour shrinkage. Intriguingly, in resistant cells, BRAFi does not induced a pigmentation signature since these cells display another AhR program; AhR-ARNT dependant. By this way, AhR directs several key BRAFi-resistant genes. At single cell level, this constitutive activation of AhR-ARNT is identified in rare cells before BRAFi-treatment of melanoma tumours and an enrichment of these alpha-cells is observed under BRAFi. Our data strongly suggest that an endogenous AhR ligand activates AhR-ARNT via the canonical AhR pocket (alpha-pocket), thus favouring BRAFi-resistant gene expression. Importantly, we identify the clinically compatible AhR antagonist, the resveratrol (RSV), able to abrogate the deleterious constitutive activation of AhR and to reduce the cellular reservoir for the relapse. Taken together, this work reveals that constitutive AhR signalling drives BRAFi resistance and constitutes a therapeutic target to achieve long-term patient survival under BRAFi. More broadly, the constitutive activation of AhR by endogenous ligands is in line with the ability of UV radiations to generate potent AhR ligands and to favour melanoma onset. Overall design: Total RNA isolated from 12 human melanoma cell lines (501Mel) after different treatments was subjected to multiplexed RNA-sequencing using Illumina NextSeq500 sequencing tehnology.
Publication Title
Sustained activation of the Aryl hydrocarbon Receptor transcription factor promotes resistance to BRAF-inhibitors in melanoma.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Ezh2 encodes the catalytic subunit of the polycomb repressive complex 2 epigenetic regulator. Its ablation in the adrenal cortex results in profound alterations of adrenal homeostasis.
Publication Title
Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Illumina HiSeq 2000
Description
Immune responses in hemophilia A patients to replacement factor VIII can be either tolerogenic or immunogenic, the latter resulting in induction of non-neutralizing anti-factor VIII antibodies or neutralizing antibodies called inhibitors. Since these inhibitors render replacement FVIII treatment essentially ineffective, preventing or eliminating them are of top priority in disease management. The extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc) is an approved therapy for hemophilia A patients. In addition, it has been reported that rFVIIIFc can induce tolerance to FVIII in hemophilia A patients that have developed inhibitors. Given that the IgG1 Fc region has the potential to interact with immune cells expressing Fc receptors and thereby affect the immune response to rFVIII, we investigated how human macrophages, expressing both Fc receptors and receptors reported to bind FVIII, respond to rFVIIIFc. We show herein that rFVIIIFc, but not rFVIII, uniquely skews macrophages towards an alternatively activated regulatory phenotype. rFVIIIFc initiates signaling events that result in morphological changes, as well as a specific gene expression and metabolic profile that is characteristic of the regulatory type Mox/M2-like macrophages. Further, these changes are dependent on rFVIIIFc-Fc receptor interactions. Our findings elucidate mechanisms of potential immunomodulatory properties of rFVIIIFc. Overall design: Human monocyte-derived macrophages (n=3) were treated with hIgG1, rFVIII or rFVIIIFc for 6h
Publication Title
Recombinant factor VIII Fc fusion protein drives regulatory macrophage polarization.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 3 Downloadable Samples
- Illumina HiSeq 2000
Description
This study aims at isolate a subpopulation of thymic epithelial cells (TECs) enrich in thymic epithelial progenitors. While recent studies have shown that bipotent TEC progenitors exist in adults, the identity of thymic epithelial progenitors (TEPCs) is still debated. Using an exclusively in vivo approach, we show that quiescent UEA1– TECs actively proliferate during thymic regeneration in 6-month-old mice and possessed a MHCIIlo Sca1hi CD49fhi CD24lo Plet1– phenotype. We then performed RNA sequencing of UEA1- quiescent (label-retaining cells, called LRCs) cells and compared them to UEA1- GFP- (nonquiescent, NonLRCs) TECs. Overall design: We analyzed 2 samples with one replicate each. Each sample contains pooled cells isolated from 11 mice to reach a minimum of 10000 cells/replicate.
Publication Title
Detection of Quiescent Radioresistant Epithelial Progenitors in the Adult Thymus.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
mESCs cultured in microfluidic chambers secrete endogneous signals which accumulate to facilitate expression of pluripotency associated genes
Publication Title
Embryonic Stem Cells Cultured in Microfluidic Chambers Take Control of Their Fate by Producing Endogenous Signals Including LIF.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 61 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Radiation is an established cause of thyroid cancer and growing evidence supports a role for H2O2 in spontaneous thyroid carcinogenesis. Little is known about the molecular programs activated by these agents in thyroid cells. We profiled the DNA damage response and cell death induced by -radiation (0.15Gy) and H2O2 (0.00250.3mM) in primary human thyroid cells and T-cells. While the two cell types had more comparable radiation responses, 3- to 10-fold more H2O2 was needed to induce detectable DNA damage in thyrocytes. At H2O2 and radiation doses incurring double-strand breaks (DSB), cell death occurred after 24hrs in T-cells, but not in thyrocytes. We next prepared thyroid and T-cells primary cultures from 8 donors operated for non-cancerous pathologies and profiled their genome-wide transcriptional response 4hr after: 1) exposure to 1 Gy radiation, 2) treatment with H2O2, or 3) no treatment. Two H2O2 doses were investigated, calibrated in each cell type as to elicit levels of single- and double-strand breaks equivalent to 1 Gy -radiation. The transcriptional responses of thyrocyte and T-cells to radiation were similar, involving DNA repair and cell death genes. In addition to this transcriptional program, H2O2 also upregulated antioxidant genes in thyrocytes, including glutathione peroxidases (GPx) at the DSB-inducing dose. By contrast, a transcriptional storm involving thousands of genes was raised in T-cells. Finally, we showed that GPx inhibition reduced the DNA damaging effect of H2O2 in thyrocytes. We conjecture that defects of anti- H2O2 protection could promote spontaneous thyroid cancers.
Publication Title
Comparative analysis of the thyrocytes and T cells: responses to H2O2 and radiation reveals an H2O2-induced antioxidant transcriptional program in thyrocytes.
Sample Metadata Fields
Sex, Age, Treatment, Subject
View Samples- Mus musculus
- 22 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Tibialis anterior muscle was damaged by cardiotoxin injection and macrophage subsets were isolated and analyzed by gene expression analysis.
Publication Title
Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair.
Sample Metadata Fields
Time
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Satellite cells are responsible for the long-term regenerative capacity of adult skeletal muscle. The diminished muscle performance and regenerative capacity of aged muscle is thought to reflect progressive fibrosis and atrophy. Whether this reduction in muscle competency also involves a diminishment in the intrinsic regulation of satellite cell self-renewal remains unknown.
Publication Title
Inhibition of JAK-STAT signaling stimulates adult satellite cell function.
Sample Metadata Fields
Specimen part
View Samples