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SRP048836
Mus musculus
2 Downloadable Samples
Illumina HiSeq 2500
Description
Hox genes are required during the morphogenesis of both vertebrate digits and external genitals.We investigated whether transcription in such distinct contexts involves a shared enhancer-containing landscape. We show that the same regulatory topology is used, yet with some tissue-specific enhancer-promoter interactions, suggesting the hijacking of a regulatory backbone from one context to the other. In addition, comparable organizations are observed at both HoxA and HoxD clusters, which separated through genome duplication in an ancestral invertebrate animal.We propose that this convergent regulatory evolution was triggered by the pre-existence of some chromatin architecture, thus facilitating the subsequent recruitment of the appropriate transcription factors. Such regulatory topologies may have both favored and constrained the evolution of pleiotropic developmental loci in vertebrates. Overall design: RNA-seq from mouse E12.5 digits cells and mouse E15.5 genital tubercle cells.
Publication Title
Convergent evolution of complex regulatory landscapes and pleiotropy at Hox loci.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Environmental enrichment has been shown to induce wholescale alterations to the gene expression profile of experimental animals
Publication Title
The impact of environmental enrichment on the murine inflammatory immune response.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Clariom S Human array (clariomshuman)
Description
Employing microarray assays, a total of 267 genes were identified that were significantly up- or downregulated in PBMCs of WT-NOD2 patients, compared to healthy donors after challenge with vitamin D (+/-D) and/or a combination (+/-LP) of LPS (lipopolysaccharide) and PGN (peptidoglycan) (p < 0.05; threshold: 2-fold change). For further analysis by real-time PCR, 12 genes with known impact on inflammation and immunity were selected that fulfilled predefined expression criteria. In a larger cohort of patients and controls, a disease-associated expression pattern, with higher transcript levels in vitamin D-treated PBMCs from 5 patients, was observed for three of these genes, CLEC5A (p < 0.030), lysozyme (LYZ; p < 0.047) and TREM1 (p < 0.023). Six genes were found to be expressed in a NOD2- dependent manner (CD101, p < 0.002; CLEC5A, p < 0.020; CXCL5, p < 0.009; IL-24, p < 0.044; ITGB2, p < 0.041; LYZ, p < 0.042). Interestingly, the highest transcript levels were observed in patients with heterozygous NOD2 mutations.
Publication Title
<i>NOD2</i>- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn's disease patients.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Mice lacking the zinc finger transcription factor Specificity protein 3 (Sp3) die prenatally in the C57Bl/6 background. To elucidate the cause of mortality we analyzed the potential role of Sp3 in embryonic heart development. Sp3 null hearts display defective looping at E10.5, and at E14.5 the Sp3 null mutants have developed a range of severe cardiac malformations. In an attempt to position Sp3 in the cardiac developmental hierarchy, we analysed the expression patterns of >15 marker genes in Sp3 null hearts. Expression of Cardiac ankyrin repeat protein (Carp) was downregulated prematurely after E12.5, while expression of the other marker genes was not affected. ChIP analysis revealed that Sp3 is bound to the Carp promoter region in vivo. Microarray analysis indicates that small molecule metabolism and cell-cell interactions are the most significantly affected biological processes in E12.5 Sp3 null myocardium. Since the epicardium showed distension from the myocardium, we studied expression of Wt1, a marker for epicardial cells. Wt1 expression was diminished in epicardium-derived cells in the myocardium of Sp3 null hearts. We conclude that Sp3 is required for normal cardiac development, and suggest that it has a crucial role in myocardial differentiation. (
Publication Title
Transcription factor Sp3 knockout mice display serious cardiac malformations.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Mutations in the genes encoding isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a variety of tumor types, resulting in production of the proposed oncometabolite, 2-hydroxyglutarate (2-HG). How mutant IDH and 2-HG alter signaling pathways to promote cancer, though, remains unclear. Additionally, there exist relatively few cell lines with IDH mutations. To examine the effect of endogenous IDH mutations and 2-HG, we created a panel of isogenic epithelial cell lines with either wild-type IDH1/2 or clinically relevant IDH1/2 mutations. Differences were noted in the ability of IDH mutations to cause robust 2-HG accumulation. IDH1/2 mutants that produce high levels of 2-HG cause an epithelial-mesenchymal transition (EMT)-like phenotype, characterized by changes in EMT-related gene expression and cellular morphology. 2-HG is sufficient to recapitulate aspects of this phenotype in the absence of an IDH mutation. In the cells types examined, mutant IDH-induced EMT is dependent on upregulation of the transcription factor ZEB1 and downregulation of the mir-200 family of microRNAs. Furthermore, sustained knockdown of IDH1 in IDH1 R132H mutant cells is sufficient to reverse many characteristics of EMT, demonstrating that continued expression of mutant IDH is required to maintain this phenotype. These results suggest mutant IDH proteins can reversibly deregulate discrete signaling pathways that contribute to tumorigenesis
Publication Title
Isocitrate dehydrogenase (IDH) mutations promote a reversible ZEB1/microRNA (miR)-200-dependent epithelial-mesenchymal transition (EMT).
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Enhanced prenatal fatty streak formation in human fetuses has been associated with maternal hypercholesterolemia. However, the possible roles of maternal genetic background and in utero environment on development of atherosclerosis in adult life have not been unraveled. We generated genetically identical heterozygous apoE-deficient mice offspring with a different maternal background to study the intrauterine effect of maternal genotype and associated hypercholesterolemia on the developing vascular system. As read out for increased atherosclerosis development in adult life, a constrictive collar was placed around the carotid artery to induce lesion formation. A significant increase in endothelial cell activation and damage was detected in the carotid arteries of heterozygous apoE-deficient fetuses with apoE-deficient mothers compared with offspring from wild type mothers, but no fatty streak formation was observed. Postnatally, all carotid arteries revealed normal morphology. In adult offspring with maternal apoE-deficiency, the constrictive collar resulted in severe lesion (9/10) development compared with no to only minor lesions (2/10) in offspring of wild type mothers. Microarray analysis showed no effect of maternal apoE-deficiency on gene expression in adult offspring. We conclude that maternal apoE-deficiency not only affects fetal arteries, but also increases the susceptibility for development of collar-induced atherosclerosis in adult life.
Publication Title
Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Illumina HiSeq 2500
Description
Somatic hypermutation (SHM) and class switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system. Overall design: IgG1 and IgM light zone (LZ) and dark zone (DZ) germinal center (GC) B cells were compared in immunized AIDcre/- IgH-96K/+ R26-LSL-YFP mice.
Publication Title
Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 20 Downloadable Samples
- Illumina HiSeq 2500
Description
Somatic hypermutation (SHM) and class switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system. Overall design: IgG1 and IgM light zone (LZ) germinal center (GC) B cells that were Nurr77-GFP+ or Nurr77-GFP- were compared in immunized AIDcre/- IgH-96K/+ Nurr77-GFP mice.
Publication Title
Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
The germinal center (GC) is a microanatomical compartment wherein high-affinity antibody-producing B cells are selectively expanded. B cells proliferate and mutate their antibody genes in the dark zone (DZ) of the GC and are then selected by T cells in the light zone (LZ) on the basis of affinity. Here, we show that T cell help regulates the speed of cell cycle phase transitions and DNA replication of GC B cells. Genome sequencing and single-molecule analyses revealed that T cell help shortens S phase by regulating replication fork progression while preserving the relative order of replication origin activation. Thus, high-affinity GC B cells are selected by a mechanism that involves prolonged dwell time in the DZ where selected cells undergo accelerated cell cycles. Overall design: To determine whether GC B cells receiving high levels of T cell help show a specific change in gene expression, we compared DZ cells in the G1 phase of the cell cycle from aDEC-OVA and control aDEC-CS treated GCs using a fluorescent ubiquitination-based cell cycle indicator (Fucci-tg). RNA sequencing revealed that T cell-mediated selection produced an increase in gene expression programs associated with the cell cycle, metabolism, including the metabolism of nucleotides, and genes downstream of c-Myc and the E2F transcription factors.
Publication Title
HUMORAL IMMUNITY. T cell help controls the speed of the cell cycle in germinal center B cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 39 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Atopic dermatitis (AD) is a common disease, with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in lack of specific treatments. The prevailing view is that AD is a biphasic, T-cell polarized disease, with Th2 predominating acute AD, and a switch to Th1 characterizing chronic disease. Identification of factors that participate in onset of lesions and maintenance of chronic lesions is critical for development of targeted therapeutics. We performed global genomic, molecular and cellular profiling of paired non-lesional, acute, and chronic skin biopsies from ten AD patients. Onset of acute lesions is associated with a striking increase in a subset of terminal differentiation proteins, specifically the IL-22-modulated S100A7-9. Correspondingly, acute disease is associated with significant increases in gene expression levels of the major Th22- (IL-22) and Th2- (IL-4, IL-31) cytokines and Th17-regulated genes (CCL20, PI3/Elafin), without significant changes in IL-17. A lesser induction of Th1- (IFN, MX-1, CXCL9-11) associated genes was detected in acute disease. Chronic skin lesions are characterized by significantly intensified activation of Th22, Th2 and Th1. Our data establish increased expression of S100A7-9 and other epidermal genes at onset of acute AD, with parallel activation of Th2 and Th22 cytokines. Our findings suggest an absence of switch mechanism in chronic disease and instead indicate that progression to chronic lesions is associated with intensified activation of immune axes that initiate onset of acute lesions, particularly Th22 and Th2. This alters the prevailing view of pathogenesis, with important therapeutic implications.
Publication Title
Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.
Sample Metadata Fields
Age, Subject
View Samples