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.
AID is required for germinal center-derived lymphomagenesis.
Specimen part
View SamplesCross-species comparative gene expression profiling was performed to identify differentially expressed genes conserved in aggressive B lymphomas.
Identification of candidate B-lymphoma genes by cross-species gene expression profiling.
Sex, Specimen part
View SamplesRadiation lung injury is characterized by early inflammation and late fibrosis. The causes underlying the chronic, progressive nature of radiation injury are poorly understood. Here, we report that the gene expression of irradiated lung tissue correlates with that observed in the lungs in aged animals. We demonstrate that NOX4 expression and superoxide elaboration is increased in irradiated lungs and pneumocytes in a dose dependent fashion.
Role of type II pneumocyte senescence in radiation-induced lung fibrosis.
Sex, Age, Specimen part, Treatment, Time
View SamplesBiased GPCR agonists are orthosteric ligands that possess pathway-selective efficacy, activating or inhibiting only a subset of the signaling repertoire of their cognate receptors. In vitro, D-Trp12,Tyr34-bPTH(7-34) (PTH-{beta}arr), a biased agonist for the type 1 parathyroid hormone receptor, antagonizes receptor-G protein coupling but activates arrestin-dependent signaling. In vivo, both PTH-{beta}arr and the conventional agonist PTH(1-34) stimulate anabolic bone formation. To understand how two PTH1R ligands with markedly different in vitro efficacy could elicit similar in vivo responses, we analyzed transcriptional profiles from calvarial bone of mice treated for 8 weeks with vehicle, PTH-{beta}arr or PTH(1-34). Treatment of wild type mice with PTH-{beta}arr primarily affected pathways that promote expansion of the osteoblast pool, notably cell cycle regulation, cell survival and migration. These responses were absent in beta-arrestin2 null mice, identifying them as downstream targets of beta-arrestin2-mediated signaling. In contrast, PTH(1-34) primarily affected pathways classically associated with enhanced bone formation, including collagen synthesis and matrix mineralization. PTH(1-34) actions were less dependent on beta-arrestin2, as might be expected of a ligand capable of G protein activation. These results illustrate the uniqueness of biased agonism in vivo and demonstrate that functional selectivity can be exploited to change the quality of GPCR efficacy.
β-arrestin-selective G protein-coupled receptor agonists engender unique biological efficacy in vivo.
Specimen part, Treatment
View SamplesMurine models have been valuable instruments in defining the pathogenesis of diabetic nephropathy (DN), but they only partially recapitulate disease manifestations of human DN, limiting their utility . In order to define the molecular similarities and differences between human and murine DN, we performed a cross-species comparison of glomerular transcriptional networks. Glomerular gene expression was profiled in patients with early type 2 DN and in three mouse models (streptozotocin DBA/2 mice, db/db C57BLKS, and eNOS-deficient C57BLKS db/db mice). Species-specific transcriptional networks were generated and compared with a novel network-matching algorithm. Three shared, human-mouse cross-species glomerular transcriptional networks containing 143 (Human-STZ), 97 (Human- db/db), and 162 (Human- eNOS-/- db/db) gene nodes were generated. Shared nodes across all networks reflected established pathogenic mechanisms of diabetic complications, such as elements of JAK-STAT and VEGFR signaling pathways . In addition, novel pathways not formally associated with DN and cross-species gene nodes and pathways unique to each of the human-mouse networks were discovered. The human-mouse shared glomerular transcriptional networks will assist DN researchers in the selection of mouse models most relevant to the human disease process of interest. Moreover, they will allow identification of new pathways shared between mice and humans.
Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli.
Age, Specimen part, Disease, Disease stage, Treatment
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation.
Specimen part
View SamplesSimilar temporal expression kinetics of transcription factors in human and mouse osteoclast differentiation evaluated by microarray
Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation.
Specimen part
View SamplesPURPOSE To identify retinal genes and their relevant expression pathways affected by intravitreal injections of dexamethasone and triamcinolone acetonide in mice at clinically relevant time points for patient care.
In vivo gene expression profiling of retina postintravitreal injections of dexamethasone and triamcinolone at clinically relevant time points for patient care.
Sex, Specimen part
View SamplesWe found that a number of Tfh cells downmodulated BCL6 protein after their development, and we sought to compare the gene expression between BCL6-hi Tfh cells and BCL6-low Tfh cells.
Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity.
Specimen part
View SamplesProper functioning of tissues requires cells to behave in uniform, well-organized ways. Conversely, many diseases involve increased cellular heterogeneity due to genetic and epigenetic alterations. Defining the mechanisms that counteract phenotypic variability is therefore critical to understand how tissues sustain homeostasis. Here, we carried out a single-cell resolution screen of zebrafish embryonic blood vessels upon mutagenesis of single microRNA (miRNA) genes and multi-gene miRNA families. We found that miRNA mutants exhibit a profound increase in cellular phenotypic variability of specific vascular traits. Genome-wide analysis of endothelial miRNA target genes identified antagonistic regulatory nodes of vascular growth and morphogenesis signaling that allow variable cell behaviors when derepressed. Remarkably, lack of such miRNA activity greatly sensitized the vascular system to microenvironmental changes induced by pharmacological stress. We uncover a previously unrecognized role of miRNAs as a widespread protective mechanism that limits variability in cellular phenotypes. This discovery marks an important advance in our comprehension of how miRNAs function in the physiology of higher organisms. Overall design: Analysis of differential genes expression in Zebrafish endothelial cells for 4 different developmental stages
MicroRNAs Establish Uniform Traits during the Architecture of Vertebrate Embryos.
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