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GSE63693
Homo sapiens
20 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Genome-wide association studies (GWAS) have identified dozens of genomic loci, whose single nucleotide polymorphisms (SNPs) predispose to prostate cancer (PCa). However, the biological functions of these common genetic variants and the mechanisms to increase disease risk are largely unknown. We integrated chromatin-IP coupled sequencing (ChIP-seq) and microarray expression profiling in the TMPRSS2-ERG gene rearrangement positive DuCaP cell model with the NHGRI GWAS PCa risk SNPs catalog, in an attempt to identify disease susceptibility SNPs localized within functional androgen receptor binding sites (ARBSs). Among the 48 GWAS index SNPs and 2,702 linked SNPs defined by the 1000G project 104 were found to be localized in the AR ChIP-seq peaks. Of these risk SNPs, rs11891426 T/G in the 7th intron of its host gene melanophilin (MLPH) was found located within a putative auxiliary ARE motif, which we found enriched in the neighborhood of canonical ARE motifs. Exchange of T to G attenuated the transcriptional activity of the MLPH-ARBS in a reporter gene assay. The expression of MLPH protein in tissue samples from prostate cancer patients was significantly lower in those with the G compared to the T allele. Moreover, a significant positive correlation of AR and MLPH protein expression levels was also confirmed in tissue samples. These results unravel a hidden link between AR and a functional PCa risk SNP rs11891426, whose allele alteration affects androgen regulation of its host gene MLPH. This study shows the power of integrative studies to pin down functional risk SNPs and justifies further investigations.
Publication Title
Putative Prostate Cancer Risk SNP in an Androgen Receptor-Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites.
Sample Metadata Fields
Cell line, Treatment, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The experiment aimed at determining the genes that are under the control of the Ikaros transcription factor in mouse splenic B1 and B2 B lymphocyte subsets. To this aim, we used Ikf/f R26-CreERT2+ (Cre+) or Ikf/f R26-CreERT2- (Cre-) mice, which correspond to mice with floxed null alleles for Ikzf1 (Heizmann et al., JEM 210:2823-32, 2013) that were crossed with the R26-CreERT2 mice, which harbor a knock-in of the cDNA encoding the tamoxifen (TAM) inducible CreERT2 recombinase in the Rosa26 gene (Badea et al, J. Neurosci 23:2314-22, 2003). 6-8 week-old mice were injected daily with TAM for 3d (50mg/kg). Mice were sacrificed 10d after the first injection, and splenic B1 and B2 B cell populations sorted by flow cytometry.
Publication Title
Ikaros Is a Negative Regulator of B1 Cell Development and Function.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 26 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Systemic lupus erythematosous (SLE) is an autoimmune disease with an important clinical and biological heterogeneity. B lymphocytes appear central to the development of SLE which is characterized by the production of a large variety of autoantibodies and hypergammaglobulinemia. In mice, immature B cells from spontaneous lupus prone animals are able to produce autoantibodies when transferred into immunodeficient mice, strongly suggesting the existence of intrinsic B cell defects during lupus. In order to approach these defects in humans, we compared the peripheral B cell transcriptomes of quiescent lupus patients to normal B cell transcriptomes.
Publication Title
B cell signature during inactive systemic lupus is heterogeneous: toward a biological dissection of lupus.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
Illumina HiSeq 2500
Description
Mature B cells leave the bone marrow as naïve B cells and migrate to the secondary lymphoid organs where they encounter the antigen for the first time. This interaction stimulates B cells to rapidly grow and form characteristic histological structures called germinal center. In the germinal centers, B cells are targeted by mechanisms of genetic editing of the immunoglobulin loci, namely somatic hypermutation and class switch recombination, undergo selection for high affinity immunoglobulin receptors and are committed to differentiate into memory B cells or plasma cells. GCs display two histological areas the dark and the light zone that have been characterized as functionally distinct compartments through which B cells recycle multiple times during the germinal center reaction. Overall design: Naïve, germinal center and memory B cells were isolated from three independent donors each.
Publication Title
MEF2B Instructs Germinal Center Development and Acts as an Oncogene in B Cell Lymphomagenesis.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 48 Downloadable Samples
- Illumina HiSeq 2500
Description
Infection-associated inflammatory stress during pregnancy is the most common cause of fetal growth restriction. Treatment strategies for protection of at-risk mothers are limited. Employing mouse models, we demonstrate that oral treatment during pregnancy with a microbial-derived immunomodulator (OM85), markedly reduces risk for fetal loss/growth restriction resulting from maternal challenge with bacterial LPS or influenza. Focusing on LPS exposure, we demonstrate that the key molecular indices of maternal inflammatory stress (RANTES, MIP-1a, CCL2, KC, G-CSF) in gestational tissues/serum, are abrogated by OM85 pretreatment. Systems-level analyses of RNASeq data revealed that OM85 pretreatment selectively tunes LPS-induced activation in maternal gestational tissues for attenuated expression of TNF-, IL1-, and IFNg- driven proinflammatory networks, without constraining Type1-IFN-associated networks central to first-line anti-microbial defense. This study suggests that broad-spectrum protection-of-pregnancy against infection-associated inflammatory stress, without compromising capacity for efficient pathogen eradication, represents an achievable therapeutic goal. Overall design: Mice were exposed to four treatment conditions (sham control, OM85 pretreatment, LPS challenge, or OM85 pretreatment followed by LPS challenge). Gene expression patterns were profiled in two different tissues (uterus and decidua). There were six animals in each experimental group.
Publication Title
Protection against maternal infection-associated fetal growth restriction: proof-of-concept with a microbial-derived immunomodulator.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 16 Downloadable Samples
- NextSeq 500
Description
Neutrophils represent a fundamental mechanism of antimicrobial resistance and inflammation 1. Moreover, neutrophils have emerged as important players in the activation, orchestration and regulation of adaptive immune responses2,3. Neutrophils are a component of the tumor microenvironment (TME) and have been prevalently shown to promote progression 4-6. On the other hand, unleashed neutrophilic effectors have also been reported to mediate anti-cancer resistance7-11. Antibody-mediated depletion used to investigate the role of neutrophils in tumor progression suffers from limitations, including duration, specificity and perturbation of the system12. We therefore used a genetic approach to investigate the role of neutrophils in primary 3-methylcholanthrene (3-MCA)-induced sarcomagenesis. Neutrophils were found to play an essential role in resistance against primary carcinogenesis by driving an interferon-? dependent type 1 immune response. Neutrophil-dependent macrophage production of IL-12p70 led to type 1 polarization of CD4- CD8- unconventional aß T cells (UTCaß) in the TME. Single cell RNAseq analysis and in vivo evidence from two preclinical sarcoma models highlight the antitumor potential of a UTCaß subset. In the TCGA cohort of human undifferentiated pleomorphic sarcomas (UPS), unlike other sarcomas, granulocyte-colony stimulating factor receptor (CSF3R) expression and a neutrophil signature were associated with better outcome and with a type 1 immune response. The positive association between high neutrophil infiltration and improved clinical outcome was confirmed in an independent UPS cohort by immunohistochemistry. Thus, neutrophils, by driving a type 1 immune response and polarization of UTCaß, mediate resistance against murine and human sarcomas. Overall design: two experimental conditions, two biological replicates for each condition
Publication Title
Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 18 Downloadable Samples
- Illumina HiSeq 2500
Description
We used RNA sequencing to characterize gene expression of Ly75+/+ B1-8hi and Ly75-/- B1-8hi B cells from the germinal center light zone (LZ) 12 h after forcing positive selection of the Ly75+/+ population with anti-DEC205-OVA. Overall design: We primed C57BL/6 hosts with OVA-alum i.p. and after 2 weeks we adoptively transferred a mixture of B1-8hi B cells in which 15% were Ly75+/+ CD45.1 (DECP) and 85% were Ly75-/- CD45.1/2 (DECN). We then immunized the animals with NP-OVA in the footpads and after 6 days we injected anti-DEC205-OVA. 12 h or 24 h after anti-DEC205-OVA injection we sorted B220+ CD38- CD95+ CD45.1+ CD45.2- CD83hi CXCR4lo (DECPLZ) and B220+ CD38- CD95+ CD45.1+ CD45.2+ CD83hi CXCR4lo (DECNLZ) cells for whole transcriptome analysis by mRNA sequencing.
Publication Title
Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 14 Downloadable Samples
- NextSeq 500
Description
We used RNA sequencing to characterize gene expression of dendritic cells from mouse lymph node that, based on LIPSTIC labeling, underwent interaction with CD4+ T cells. Overall design: Antigen pulsed dendritic cells (DCs) were transferred into recipient mice, followed by antigen specific CD4+ T cells. Forty-eight hours after T cell transfer, endogenous dendritic cells were isolated by facs sorting from mouse lymph node and analyzed based on their in vivo LIPSTIC labeling.
Publication Title
Monitoring T cell-dendritic cell interactions in vivo by intercellular enzymatic labelling.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 28 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Most human B cell lymphomas (B-NHL) are derived from germinal centers (GCs), the structure where B-cells undergo class switch recombination (CSR) and somatic hypermutation (SHM) and are selected for high-affinity antibody production. The pathogenesis of B-NHL is associated with distinct genetic lesions, including chromosomal translocations and aberrant somatic hypermutation, which appear to arise from mistakes occurring during CSR and SHM. To ascertain the role of CSR and SHM in lymphomagenesis, we crossed three oncogene-driven (MYC, BCL6, MYC/BCL6) mouse models of B cell lymphoma with mice lacking activation-induced cytidine deaminase (AID), the enzyme required for both processes.
Publication Title
AID is required for germinal center-derived lymphomagenesis.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) (collectively, over 70% of all lymphoma diagnoses), these mutations are highly recurrent and appear early during transformation, possibly in pre-malignant precursors. Here we show that FL- and DLBCL-associated MLL2 mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in normal germinal-center (GC) B cells and DLBCL, consistent with the enrichment of MLL2 binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Mll2 early during B cell development, but not after initiation of the GC reaction, leads to increased percentages and numbers of GC B cells, which feature a distinct transcriptional profile defined by the enrichment of cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Mll2-deficient B cells exhibit proliferative advantage and accumulation in the S phase of the cell cycle, which is influenced by the number of cell divisions. While GC-specific loss of Mll2 was not sufficient to initiate malignant transformation, compound Mll2-deficient/BCL2-transgenic mice displayed an increased incidence of clonal lymphoproliferations resembling the features of human FL and DLBCL. These findings suggest that early MLL2 loss favors BCL2-induced lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of MLL2-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events.
Publication Title
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.
Sample Metadata Fields
Sex, Specimen part
View Samples