During chronic viral infection, the inflammatory function of CD4 T cells becomes gradually attenuated. Concurrently, Th1 cells progressively acquire the capacity to secrete the cytokine IL-10, a potent suppressor of antiviral T cell responses. To determine the transcriptional changes that underlie this T cell adaption process, we applied a single-cell RNA-sequencing approach and assessed the heterogeneity of IL-10-expressing CD4 T cells during chronic infection. Unexpectedly, our analyses revealed an IL-10-producing population with a robust Tfh-signature. Using IL-10 and IL-21 double-reporter mice, we further demonstrate that IL-10+IL-21+co-producing Tfh cells arise predominantly during chronic but not acute LCMV infection. Importantly, depletion of IL-10+IL-21+co-producing CD4 T cells or deletion of Il10 specifically in Tfh cells resulted in impaired humoral immunity and viral control. Mechanistically, B cell-intrinsic IL-10 signaling was required for sustaining germinal center reactions. Lastly, we demonstrate that IL-27 and type I IFNs differentially regulate the formation of this protective IL-10-producing Tfh subset. Thus, our findings elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection. Overall design: One sample prepared using 10x Genomics Chromium platform
Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection.
Specimen part, Subject, Time
View SamplesWe established gene expression profiles of diagnostic bone marrow samples of monozygotic twins with acute lymphoblastic leukemia. We established technical duplicates for each twin.
Prenatal origin of separate evolution of leukemia in identical twins.
Sex, Specimen part, Disease, Disease stage
View SamplesMicroRNA-520f regulates EMT, as it activates CDH1 (mRNA) and E-cadherin (protein) expression, and it suppresses tumor cell invasion. We have characterized miR-520f target genes through whole genome transcriptional profiling of miRNA transfected pancreas cancer cells (PANC-1).
miRNA-520f Reverses Epithelial-to-Mesenchymal Transition by Targeting <i>ADAM9</i> and <i>TGFBR2</i>.
Cell line, Treatment
View SamplesStudies investigating the causes of autism spectrum disorder (ASD) point to genetic as well as epigenetic mechanisms of the disease. Identification of epigenetic processes that contribute to ASD development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here we identify the bromodomain and extra-terminal domain containing transcriptional regulators (BETs) as epigenetic drivers of an ASD-like disorder in mice. We found that the pharmacological suppression of the BET proteins by a novel, highly selective and brain-permeable inhibitor, I-BET858, leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome in mice. Many of the I-BET858 affected genes have been linked to ASD in humans thus suggesting the key role of the BET-controlled gene network in ASD. Our studies also suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.
Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice.
Specimen part
View SamplesE47 represses Foxp3 transcription, albeit indirectly through the activation of unknown negative regulatory of Foxp3 transcription.
Id3 Maintains Foxp3 Expression in Regulatory T Cells by Controlling a Transcriptional Network of E47, Spi-B, and SOCS3.
Age, Specimen part
View SamplesIn chicks, the avian homologue of the early growth response protein-1 (ZENK) has been shown to be increased in a special cell type of the retina, the glucagonergic amacrine cells, under conditions that lead to a reduction in eye growth (myopic defocus, recovery of myopia) and decreased under conditions that enhance ocular growth (hyperopic defocus, form-deprivation). The investigation of Egr-1 knock-out mice showed that homozygous knock-out mice with no functional Egr-1 protein developed relative axial myopia at the age of 42 and 56 days, compared to heterozygous- and wildtype Egr-1 knock-out mice.
Microarray analysis of retinal gene expression in Egr-1 knockout mice.
Sex, Age, Specimen part
View SamplesThe retina plays an important regulatory role in ocular growth. To screen for new retinal candidate genes that could be involved in the inhibition of ocular growth, we used chick microarrays to analyze the changes in retinal mRNA expression after myopic defocus was imposed by positive lens-wear.
Microarray analysis of retinal gene expression in chicks during imposed myopic defocus.
Sex, Age
View SamplesIn D. melanogaster males, X chromosome monosomy is compensated by chromosome-wide transcription activation. We found that complete dosage compensation during embryogenesis takes surprisingly long. Although the activating Dosage Compensation Complex (DCC) associates with the chromosome and acetylates histone H4 early, many genes are not compensated. Acetylation levels on gene bodies continue to increase for several hours after gastrulation in parallel with progressive compensation. Constitutive genes are compensated earlier than developmental genes. Remarkably, later compensation correlates with longer distances to DCC binding sites. This time-space relationship suggests that DCC action on target genes requires maturation of the active chromosome compartment. Overall design: RNA-seq in 8 embryonic stages in total 54 single embryos.
Progressive dosage compensation during Drosophila embryogenesis is reflected by gene arrangement.
Specimen part, Subject
View SamplesThe statsitcal model, latent pathway identification analysis (LPIA), was implemented for the analysis of A549 lung carcinoma cells treated with geldanamycin. Control and treated samples were assayed with Affymetrix HG_U133_plus_2 arrays and analyzed using LPIA. LPIA looks for statistically signcant evidence of dysregulation in a network of pathways constructed in a manner that explicitly links pathways through their common function in the cell. Geldanamycin (geld) is known to inhibit the molecular chaperone protein, Hsp90, and plays a role in preventing the malignant transformation and proliferation of healthy cells during oncogenesis. LPIA successfully identified pathways specific to geldanamycin effects at the gene transcription level.
Network-based prediction for sources of transcriptional dysregulation using latent pathway identification analysis.
Specimen part, Cell line, Time
View SamplesTransplanting renal allografts represents the major curative treatment of chronic renal failure. Despite recent advances in immunosuppressive therapy, long-term survival of allografts remains a major clinical problem. Kidney function depends in part on transport proteins such as MRP2 (ABCC2) which facilitates renal secretion of amphiphilic exogenous and endogenous compounds. Inherited variants of genes not related to the immune system have been shown to modify the outcome after renal transplantation. We investigated whether ABCC2 gene variants in the donor kidney affect renal graft function.
Multidrug resistance-related protein 2 genotype of the donor affects kidney graft function.
Sex
View Samples