DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID
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ABSTRACT:
PROVIDER: PRJNA293379 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR2175680.fastq.gz | Fastqsanger.gz | |||
| SRR2175690.fastq.gz | Fastqsanger.gz | |||
| SRR2175700.fastq.gz | Fastqsanger.gz | |||
| SRR2175710.fastq.gz | Fastqsanger.gz | |||
| SRR2175720.fastq.gz | Fastqsanger.gz |
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Project description:Changes in DNA methylation are required for the formation of germinal centers (GC), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated recently in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCB) isolated from wild type (WT) and AID-deficient (Aicda-/-) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda-/- animals. Differentially methylated cytosines (DMCs) between GCB and naïve B cells (NB) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells. ERRBS and RNA-seq of wild type and Aicda knockout murine naive and germinal center B cells. ERRBS of human naive and germinal center B cells
2015-09-15 | E-GEOD-71702 | biostudies-arrayexpress
Project description:Changes in DNA methylation are required for the formation of germinal centers (GC), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated recently in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCB) isolated from wild type (WT) and AID-deficient (Aicda-/-) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda-/- animals. Differentially methylated cytosines (DMCs) between GCB and naïve B cells (NB) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells.
2015-09-15 | GSE71702 | GEO
Project description: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.
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Project description:SENP1 Regulates Germinal Center B Cell Responses through PAX5-deSUMOylation mediated AID expression
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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.
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Project description:Productive B cell responses are critical to protect a host from infection. The spleen and lymph nodes are populated by resting follicular B cells, which can enter germinal centers upon antigen encounter. Once in the germinal center, B cells migrate between the dark and light zones, where they undergo somatic hypermutation and selection, respectively. While germinal center B cells have been studied, an intense molecular understanding of these cells/subsets (and the differences between them) is lacking.
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Project description:Changes in DNA methylation are required for the formation of germinal centers (GCs), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCBs) isolated from wild-type (WT) and AID-deficient (Aicda(-/-)) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda(-/-) animals. Differentially methylated cytosines (DMCs) between GCBs and naive B cells (NBs) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID, and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells.
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Project description:Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which approximately 25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis discards AID involvement. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.
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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.
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