Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptional Landscape of B cell Early Activation

ABSTRACT: The physiological responses to B cell receptors (BCR) and Toll-like receptors (TLRs) so vital to immunity are well known but the transcriptional signatures and regulatory mechanisms that initiate activation and release cells from quiescence remain unclear. Here, we show that BCR- or TLR-mediated activation of B cells involves a large shared transcriptional signature and a smaller subset of distinct signal-specific transcriptional responses. Signal-specific transcription is observable within 2 hours of ligand exposure; suggesting different modes of activation begin soon after ligand binding and long before the well-documented BCR and TLR-dependent physiological responses occur. Ligand-specific differences in regulatory mechanisms including RNA Pol II recruitment, activating (H3K4me3) and repressing (H3K27me3) histone marks, transcription factor binding sites in responsive gene promoters, and miRNA expression were observed. These results begin to define the transcriptional landscape of early B cell activation revealing more ligand-specific regulation and character than occurs much earlier than previously expected.

ORGANISM(S): Mus musculus

PROVIDER: GSE61608 | GEO | 2015/04/30

SECONDARY ACCESSION(S): PRJNA261681

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcriptional Landscape of B cell Early Activation

Project description:The physiological responses to B cell receptors (BCR) and Toll-like receptors (TLRs) so vital to immunity are well known but the transcriptional signatures and regulatory mechanisms that initiate activation and release cells from quiescence remain unclear. Here, we show that BCR- or TLR-mediated activation of B cells involves a large shared transcriptional signature and a smaller subset of distinct signal-specific transcriptional responses. Signal-specific transcription is observable within 2 hours of ligand exposure; suggesting different modes of activation begin soon after ligand binding and long before the well-documented BCR and TLR-dependent physiological responses occur. Ligand-specific differences in regulatory mechanisms including RNA Pol II recruitment, activating (H3K4me3) and repressing (H3K27me3) histone marks, transcription factor binding sites in responsive gene promoters, and miRNA expression were observed. These results begin to define the transcriptional landscape of early B cell activation revealing more ligand-specific regulation and character than occurs much earlier than previously expected. CD43- mouse resting B cells were stimulated with ligands against the B cell receptor and TLR4 (LPS). RNA-sequencing was performed to describe differential transcription and ChIP-sequencing was performed to describe regulatory mechanism responses.

2015-04-30 | E-GEOD-61608 | biostudies-arrayexpress

Ligand-induced shifts in conformational ensembles that predict transcriptional activation

Project description:Nuclear receptors function as ligand-regulated transcription factors whose ability to regulate diverse physiological processes is closely linked with conformational changes induced upon ligand binding. Understanding how conformational populations of nuclear receptors are shifted by various ligands could illuminate strategies for the design of synthetic modulators to regulate specific transcriptional programs. Here, we investigate ligand-induced conformational changes using a reconstructed, ancestral nuclear receptor. By making substitutions at a key position, we engineer receptor variants with altered ligand specificities. We use atomistic molecular dynamics (MD) simulations with enhanced sampling to generate ensembles of wildtype and engineered receptors in combination with multiple ligands, followed by conformational analysis and prediction of ligand activity. We combine cellular and biophysical experiments to allow correlation of MD-based predictions with functional ligand profiles, as well as elucidation of mechanisms underlying altered transcription in receptor variants. We determine that conformational ensembles accurately predict ligand responses based on observed population shifts, even within engineered receptors that were constitutively active or transcriptionally unresponsive in experiments. These studies provide a platform which will allow structural characterization of physiologically-relevant conformational ensembles, as well as provide the ability to design and predict transcriptional responses in novel ligands.

2022-10-12 | PXD036076 | Pride

Ikaros prevents autoimmunity by promoting anergy induction and restraining Toll-like receptor signaling in B cells

Project description:Establishment of a diverse B-cell receptor (BCR) repertoire by V(D)J recombination generates autoreactive B-cells that are eliminated by central tolerance in the bone marrow or down-regulate their BCR responsiveness to self-antigen during anergy induction in peripheral B-cells. The loss of anergy combined with hyperactivation of nucleic acid-sensing Toll-like receptors (TLRs) is thought to break B-cell tolerance leading to autoimmunity, although the transcriptional factors controlling these processes are still unknown. Here, we describe a critical role of Ikaros in promoting B-cell anergy and restraining TLR signaling by analyzing mice with specific deletion of Ikaros in mature B-cells, which resulted in systemic autoimmunity. While regulating many anergy-associated genes, Ikaros also activated the Zfp318 gene, implicated in down-tuning of the BCR responsiveness by shifting expression from IgM to IgD in anergic B-cells. TLR signaling was hyperactive in Ikaros-deficient B-cells, which failed to up-regulate feedback inhibitors of the MyD88-NF-?B signaling pathway. Systemic inflammation was lost upon expression of a non-self-reactive BCR or loss of MyD88 in Ikaros-deficient B-cells, which identified Ikaros as a guardian preventing autoimmunity by coordinately regulating anergy induction and TLR signaling.

2019-07-01 | GSE122313 | GEO

Cannabinoid receptor 2 is necessary to induce toll-like receptor-mediated microglial activation.

Project description:The tight regulation of microglia activity is key for precise responses to potential threats, while uncontrolled and exacerbated microglial activity is neurotoxic. Microglial toll-like receptors (TLRs) are indispensable for sensing different types of assaults and triggering an innate immune response. Cannabinoid receptor 2 (CB2) signaling is a key pathway to control microglial homeostasis and activation, and its activation is connected to changes in microglial activity. We aimed to investigate how CB2 signaling impacts TLR-mediated microglial activation. Here, we demonstrate that deletion of CB2 causes a dampened transcriptional response to prototypic TLR ligands in microglia. Loss of CB2 results in distinct microglial gene expression profiles, morphology, and activation. We show that the CB2-mediated attenuation of TLR-induced microglial activation is p38 MAPK-dependent. Taken together, we demonstrate that CB2 expression and signaling are necessary to fine-tune TLR-induced activation programs in microglia.

2021-08-23 | GSE173337 | GEO

Next Generation Sequencing analysis of BCR-induced gene expression in adult and neonatal splenic B cells

Project description:Newborns are unable to reach the adult-level humoral immune response partly due to the potent immunoregulatory role of IL-10. IL-10 expression is controlled by various transcription factors including nuclear factor-κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), and GATA binding protein 3 (GATA3) depending on the upstream signaling pathways and cell types. In B cells, IL-10 production has been shown to be activated by B cell receptor (BCR) engagement, CD40 ligand, TLR agonists, IL-1β and IL-6. We have shown increased IL-10 production by BCR-stimulated neonatal B cells compared to adult counterparts. To gain insight into the underlying mechanisms of enhanced IL-10 production in BCR-stimulated neonatal B cells, we performed RNA sequencing and Gene Set Enrichment Analysis for adult and neonatal B cells following BCR engagement. To identify signaling pathways uniquely activated by neonatal BCR, we compared adult and neonatal B cell data using hallmark gene sets from the Molecular Signatures database (MSigDB) C5 gene ontology (GO) collection. Pathways enriched in neonatal B cells included cytokine receptor signaling pathways leading to Signal Transducer And Activator Of Transcription (STAT) protein activation. We also conducted GSEA using the MSigDB C3 transcription factor targets (TFT) hallmark gene collection to identify transcription factors uniquely activated in neonatal B cells. This analysis revealed that target gene sets for STAT3, STAT5A and STAT5B were highly enriched in neonatal B cells, suggesting that these STAT proteins were activated in neonatal B cells after BCR engagement.

2022-04-20 | GSE200955 | GEO

Rodríguez-Jorge2019 - Boolean model of combined TCR and TLR5 signaling for CD4 + T cell activation

Project description:CD4+ T cells recognize antigens through their T cell receptors (TCRs); however, additional signals involving costimulatory receptors, for example, CD28, are required for proper T cell activation. Alternative costimulatory receptors have been proposed, including members of the Toll-like receptor (TLR) family, such as TLR5 and TLR2. To understand the molecular mechanism underlying a potential costimulatory role for TLR5, we generated detailed molecular maps and logical models for the TCR and TLR5 signaling pathways and a merged model for cross-interactions between the two pathways. Furthermore, we validated the resulting model by analyzing how T cells responded to the activation of these pathways alone or in combination, in terms of the activation of the transcriptional regulators CREB, AP-1 (c-Jun), and NF-κB (p65). Our merged model accurately predicted the experimental results, showing that the activation of TLR5 can play a similar role to that of CD28 activation with respect to AP-1, CREB, and NF-κB activation, thereby providing insights regarding the cross-regulation of these pathways in CD4+ T cells.

2021-04-06 | MODEL1903260003 | BioModels

Rodríguez-Jorge2019 - Boolean model of TCR signaling for CD4 + T cell activation

2021-04-06 | MODEL1903260001 | BioModels

Whole-Genome Gene Expression Bead Array analysis of Toll-like receptor 2/8 stimulated human monocytes

Project description:Monocytes and macrophages are essential cells in the early response in their capacity as ubiquitous phagocytic cells. They phagocytose microorganisms or damaged cells and sense pathogen/damage-associated molecular patterns (PAMPs/DAMPs) through innate receptors such as Toll-like receptors (TLRs). We investigated a phenomenon where co-signaling from TLR2 and TLR8 in human primary monocytes provides a distinct immune activation profile compared to signaling from either TLR alone. Comparison of gene signatures induced by either stimulus alone or together, show that co-signaling result in downstream differences in regulation of signaling and gene transcription. To investigate the interaction of TLR2 and TLR8 stimulation primary human monocytes isolated from buffy coat were stimulated with TLR2/6 ligand FSL-1 and/or TLR7/8 ligand CL075 and the gene expression monitored at 1,2 and 3h post stimulation.

2018-03-09 | E-MTAB-6222 | biostudies-arrayexpress

Transcription profiling of mouse AM-14 B cells stimulated through the B cell receptor (BCR) and/or Toll-like receptors (TLR)

Project description:We have previously shown that rheumatoid factors (RF) produced by Fas-deficient autoimmune-prone mice typically bind autologous IgG2a with remarkably low affinity. Nevertheless, B cells representative of this RF population proliferate vigorously in response IgG2a/chromatin immune complexes through a mechanism dependent on the sequential engagement of the BCR and Toll-like receptor 9 (TLR9). To more precisely address the role of both receptors in this response, we analyzed the signaling pathways activated in AM14 B cells stimulated with these complexes. We found that the BCR not only serves to direct the chromatin complex to an internal compartment where it can engage TLR9 but also transmits a suboptimal signal that in combination with the signals emanating from TLR9 leads to NF?B activation and proliferation. Importantly, engagement of both receptors leads to the upregulation of a group of gene products, not induced by the BCR or TLR9 alone, that include IL-2. These data indicate that autoreactive B cells, stimulated by a combination of BCR and TLR9 ligands, acquire functional properties that may contribute to the activation of additional cells involved in the autoimmune disease process. Experiment Overall Design: 15 Samples, 3 replicates for each treatment

2008-06-15 | E-GEOD-6674 | biostudies-arrayexpress

Sorted B cells from mice treated with MPL and/or R837

Project description:Many successful vaccines induce persistent antibody responses that can last a lifetime. The mechanisms by which they do so remain unclear, but emerging evidence suggests that activate dendritic cells (DCs) via Toll-like receptors (TLRs). For example, the yellow fever vaccine YF-17D, one of the most successful empiric vaccines ever developed, activates DCs via multiple TLRs to stimulate pro-inflammatory cytokines. Triggering specific combinations of TLRs in DCs can induce synergistic production of cytokines, which results in enhanced T cell responses, but its impact on antibody responses remain unknown. Learning the critical parameters of innate immunity that programs such antibody responses remains a major challenge in vaccinology. We demonstrated that immunization of mice with synthetic nanoparticles containing antigens plus Toll-like receptor (TLR) ligands 4 (MPL) + 7 (R837) induces synergistic increases in antigen-specific, neutralizing antibodies compared to immunization with a single TLR ligand. To determine whether there was any early programming of B cells, we isolated isotype switched, TCRbeta-CD11b-CD19+IgD-IgG+ B cells by FACS at 7 days post immunization with nanoparticles containing various adjuvants plus OVA, and performed microarray analyses to assess their molecular signatures. Two independent sets of samples at day 7 post-treatment were used in our analyses. Each set is comprised by B-cells from mice treated with MPL + R837 or from those treated with either individual MPL or R837 alone.

2010-12-01 | E-GEOD-25677 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data