Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

SENP1 Regulates Germinal Center B Cell Responses through PAX5-deSUMOylation mediated AID expression

ABSTRACT: Humoral immunity depends on germinal center reaction where B cells are tightly controlled for class switch recombination (CSR) and somatic hypermutation, and finally generated into plasma and memory B cells. However, how protein SUMOylation control the key events of GC B cells remains to be understood. Here, we show that SUMO-specific protease 1 (SENP1) is upregulated in GC B cells. Selective ablation of Senp1 within GC B cells led to defective dark zone versus light zone GC B organization, impaired IgG1-switched GC B cells, and compromised antibody response. In addition, the formation of antigen-specific plasma and memory B cells were also diminished when SENP1 was deleted in GC B cells. Mechanistically, SENP1 was indispensable for expression of activation-induced cytidine deaminase (AID). SENP1-mediated Paired box protein 5 deSUMOylation suppressed the transcription to AID, which might be responsible for defective CSR in vivo. Our study not only established the importance of protein SUMOylation for the maintenance of GC B cell function but also clarified a novel mechanism to the modulation of AID expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE227067 | GEO | 2024/06/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Transcription factor Ascl2 promotes geminal center B cell responses through directly regulating AID transcription

Project description:During germinal center (GC) reactions, activated B cells undergo clonal expansion and functional maturation to produce high-affinity antibodies, and differentiate into plasma and memory cells, accompanied with class-switching recombination (CSR) and somatic hypermutation (SHM). Activation-induced deaminase (AID) is responsible for both CSR and SHM in GC B cells. Transcriptional mechanisms underlying AID regulation and GC B cell reactions are still not well understood. Here, we show that expression of Ascl2 transcription factor is upregulated in GC B cells. Ectopic expression of Ascl2 promotes GC B cell development and enhances antibody production as well as affinity maturation. Conversely, deletion of Ascl2 in B cells impairs the germinal center response. Genome-wide analysis reveals that Ascl2 directly regulates GC B cell-related genes, including AID; ectopic expression of AID in Ascl2-deficient B cells rescues their antibody defects. Thus, Ascl2 regulates AID transcription and promotes germinal center B cell responses.

2021-03-30 | GSE169416 | GEO

SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation

Project description:The mechanism underlying RIPK1-driven cell death and inflammation, a key process in the progression of nonalcoholic steatohepatitis, remains unclear. Here we identified SENP1, a SUMO-specific protease, as a key endogenous inhibitor of RIPK1. SENP1 is progressively reduced in proportion to NASH severity in patients. Hepatocyte-specific SENP1-knockout mice develop spontaneous NASH-related phenotypes in a RIPK1 kinase-dependent manner. We demonstrate that SENP1 deficiency sensitizes cells to RIPK1 kinase-dependent apoptosis by promoting RIPK1 activation following TNFα stimulation. Mechanistically, SENP1 deSUMOylates RIPK1 in TNF-R1 signaling complex (TNF-RSC), keeping RIPK1 in check. Loss of SENP1 leads to SUMOylation of RIPK1, which re-orchestrates TNF-RSC and modulates the ubiquitination patterns and activity of RIPK1. Notably, genetic inhibition of RIPK1 effectively reverses disease progression in hepatocyte-specific SENP1-knockout male mice with high-fat-diet-induced nonalcoholic fatty liver. We propose that deSUMOylation of RIPK1 by SENP1 provides a pathophysiologically relevant cell death-restricting checkpoint that modulates RIPK1 activation in the pathogenesis of nonalcoholic steatohepatitis.

2022-10-20 | GSE193509 | GEO

Plasmablasts and germinal center founder cells developing in vivo

Project description:A range of cellular interactions and cytokines influence immunoglobulin class switch recombination (CSR), which occurs both in extrafollicular antibody responses and germinal centers. This study addresses where CSR occurs during extrafollicular responses, allowing identification of the cellular interactions and cytokine-producing cells that influence CSR in vivo. The response in mice of B cells specific for 4-hydroxy-3-nitrophenyl-acetyl (NP) to NP-Ficoll was analyzed. Immunohistology and flow cytometry confirm responding NP-binding cells move to the outer T zone of the spleen and start dividing there on the second day. During the third day they move either to follicles as germinal center founding cells, or extrafollicular foci as plasmablasts. Analysis of expression of AID, Bcl-6 and Blimp-1 mRNA in single NP-binding cells indicates a proportion of T zone B blasts express AID transiently without Bcl-6 and these cells are shown to undergo CSR. By contrast Blimp-1+ cells emerging on the third day and were universally AID- and hence unable to initiate CSR. Bcl-6 mRNA without protein, expressed by 40% of naïve NP-binding cells, is rapidly downregulated. Bcl-6 and AID are coexpressed by germinal centre founding cells only on moving to follicles during the third day after immunization. Keywords: TaqMan Low Density Array

2008-01-01 | GSE7744 | GEO

Gene expression analysis of B-NHL from λMYC, λMYC/IµHABCL6, λMYC/AIDKO and λMYC/IµHABCL6/AIDKO mouse models

Project 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. We show that AID deficiency prevents BCL6-dependent, GC-derived B-NHL, while it has no impact on the formation of MYC-driven, pre-GC lymphomas. Accordingly, abrogation of AID is associated with the disappearance of both CSR- and SHM-mediated structural alterations, including cMYC-IgH chromosomal translocations and aberrant SHM. These results demonstrate that AID is required for GC-derived lymphomagenesis, providing direct support to the notion that errors in AID-mediated antigen-receptor gene modification events represent major contributors to the pathogenesis of human B-NHL. Keywords: Phenotypic characterization of tumors developing in oncogene-driven mouse models of lymphomas

2007-11-01 | GSE9249 | GEO

Id3 Orchestrates Germinal Center B Cell Development

Project description:Previous studies have demonstrated that E-proteins induce AID expression in activated B cells. Here we have examined the role of Id3 in germinal center (GC) cells. We found that Id3 expression is high in follicular B-lineage cells but declines in GC cells. Immunized mice depleted for Id3 expression displayed a block in germinal center B cell maturation, showed reduced numbers of marginal zone B cells and class switched cells, were associated with decreased antibody titers and lower numbers of plasma cells. In vitro Id3-depleted B cells displayed a defect in class switch recombination. Whereas AID levels were not altered in Id3-depleted activated B cells, the expression of a subset of genes encoding for signaling components of antigen receptor, cytokine receptor and chemokine receptor mediated signaling was significantly impaired. We propose that during the GC reaction Id3 levels decline to activate the expression of genes encoding for signaling components that mediate B cell receptor and or cytokine-mediated signaling to promote the differentiation of GC B cells.

2016-08-18 | GSE84374 | GEO

Transcriptional profiles of knockouts of m6A writer and readers in Germinal Center B cells

Project description:We performed RNA-seq (MARS-seq) on germinal center (GC) light zone and dark zone B cells sorted to purity from freshly dissociated mouse popliteal lymph nodes immunized with NP-KLH for 7 to 14 days. Germinal center B cell subsets were gated as follows: Dump (CD8, CD4, F4/80, Gr-1)- B220+ CD38- GL-7+ FAS+. Dark zone GC cells were in addition CD86lo, CXCR4hi; LZ cells were in addition CD86hi, CXCR4lo. Three different mouse models were used: AID-cre Mettl3-flox, AID-cre Ythdf2-flox, Igf2bp3-knockout. We used these data to derive differentially expressed genes between B cell subsets of control and knockout genotypes. We also performed m6A-IP on ex vivo activated wild type B cells and determined the m6A targets in B cells. These studies revealed that the GC response depends on m6A RNA methylation and the functions of specific methyl-readers Ythdf2 and Igf2bp3.

2021-07-21 | GSE180359 | GEO

IL-23 promotes a coordinated B-cell germinal center program for class-switch recombination to IgG2b in BXD2 mice

Project description:IL-23 promotes autoimmune disease including Th17 CD4 T-cell development and autoantibody (autoAb) production. Here, we show that a deficiency of the p19 component of IL-23 in autoimmune BXD2 (BXD2-p19−/−) mice leads to an imbalance of the follicular T-helper cell program with a shift from Tfh-IL-17 to Tfh-IFN-ɣ. Although the germinal center (GC) size and number of GC B cells remained the same, BXD2-p19−/− mice exhibited a lower class-switch recombination (CSR) program in the GC B cells, leading to a lower serum levels of IgG2b. Single cell transcriptomics analysis revealed that while GC B cell expression of Ifngr1 and Il21r genes exhibited a synchronized expression pattern with plasma cell program genes, Il17ra exhibited a synchronized expression pattern with pre-plasmablast GC program genes. Down-regulation of Ighg2b in BXD2-p19−/− GC B cells was associated with decreased expression of CSR-related base excision repair genes that were otherwise predominantly expressed by Il17ra+ cells compared to Ifngr1+ GC B cells in BXD2 mice. Together, these results suggest that although IL-23 is dispensable for GC formation, it is essential for development of the Tfh-IL17 Tfh subpopulation, which drives CSR-related base excision repair genes during the pre-plasmablast GC stage of development.

2020-05-14 | GSE145922 | GEO

SENP6 in OCP maintenance

Project description:To understand the role of sumoylation/desumoylation pathway in skeletla development and homeostasis, we compared the transcriptomic profiles of primary rib chondrocytes from WT vs.Dermo1-Cre;Senp6f/f mice.

2017-11-28 | GSE102856 | GEO

Expression data from IgE+ and IgG1+ B lymphocytes in mice infected with Nippostrongylus brasiliensis

Project description:The mechanisms involved in the maintenance of memory IgE responses are poorly understood, and the role played by germinal center (GC) IgE cells in these memory responses is particularly unclear. IgE B-cell differentiation is characterized by a transient GC phase, a bias towards the plasma cell (PC) fate, and dependence on sequential switching for the production of high-affinity IgE. We show here that IgE GC B cells are unfit to undergo the conventional GC differentiation program due to impaired B-cell receptor function and increased apoptosis. IgE GC cells fail to populate the GC light zone and are unable to contribute to the memory and long-lived PC compartments. Furthermore, we demonstrate that direct and sequential switching are linked to distinct B-cell differentiation fates: direct switching generates IgE GC cells, whereas sequential switching gives rise to IgE plasma cells. We propose a comprehensive model for the generation and memory of IgE responses. The purpose of this analysis was to: 1) identify expression differences between IgE and IgG1 B lymphocytes, 2) identify GC Dark Zone (DZ) and Light Zone (LZ) signatures of IgG1 GC cells. For that purpose, we compared in one experiment the gene expression patterns of IgE germinal center (GC) cells, IgG1 GC cells, IgE plasma cells (PC), IgG1 PC and naïve cells. In a second experiment, we compared the expression of IgG1 DZ GC cells with that of IgG1 LZ GC cells. Triplicates obtained from independent sorting experiments were used for all samples except two (IgG1 PC=2 samples; IgE PC=4 samples). Each sample was obtained from a pool of three individual mice. The mice used in the experiment were CeGFP BALB/c mice infected with the parasite N. brasiliensis. CeGFP mice carry an IRES-GFP KI cassette in the 3'UTR of membrane IgE. In these mice, GFP expression marks IgE cells, and a population of IgG1 cells with a rearrangement to Cepsilon in the non-productive (VDJ negative) IgH chromosome.

2013-10-31 | E-GEOD-49033 | biostudies-arrayexpress

Gene expression comparison, WT and PDAP1-deficient primary B lymphocytes

Project description:Class switch recombination (CSR) and somatic hypermutation (SHM) are antibody gene diversification reactions occurring in mature B cells that are essential for protective humoral immunity. CSR and SHM are initiated following activation by the antigen, and are dependent on efficient induction of activation-induced cytidine deaminase (AID). Therefore, mature B cell viability and fitness are crucial to mount effective immune responses. Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation, and ensures efficient antibody diversification by promoting their survival and optimal function.

2020-06-19 | GSE141876 | GEO

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