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DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE71702 | GEO | 2015/09/15

SECONDARY ACCESSION(S): PRJNA293379

REPOSITORIES: GEO

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DNA Methylation Dynamics of Germinal Center B Cells Are Mediated by AID

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

Transcription profiling of mouse naive B cells and gernimal center B cells

Project description:Activation-induced cytidine deaminase (AID) is essential for the generation of antibody memory but also targets oncogenes among others. We investigated the transcriptional regulation of the AID gene, Aicda, in the class switchâinducible CH12F3-2 cells, and found that the Aicda regulation involves derepression by several layers of positive regulatory elements in addition to the 5â promoter region. The 5â upstream region contains functional motifs for the response to signaling by cytokines, CD40-ligand, or stimuli that activate NF-ÎºB. The first intron contains functional binding elements for the ubiquitous silencers c-Myb and E2f and for B cellâspecific activator Pax5 and E-box-binding proteins. To confirm involvement of these transcription factors in Acida regulation, we examined their expression profile of these factors in naÃ¯ve and germinal center B cells. Experiment Overall Design: NaÃ¯ve B cells were defined as B220+PNA-Fas- and germinal center B cells were defined as B220+PNA+Fas+ cells. These cells were purified from immunized mouse lymph nodes or mouse Peyer's patches by using FACS Aria. Samples are as follows: pLN GC, pLN naÃ¯ve, PP GC, PP naÃ¯ve, (each 1 sample, prepared from pooled 3-5 mice)

2009-11-10 | E-GEOD-18746 | biostudies-arrayexpress

AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis

Project description:Epigenetic heterogeneity is emerging as a significant phenotypic feature of tumors. In diffuse large B-cell lymphomas (DLBCLs), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the biological mechanisms driving epigenetic heterogeneity remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that deaminates and facilitates demethylation of DNA methyl-cytosines in germinal center (GC) B-cells, is required for DLBCL pathogenesis and linked to inferior clinical outcomes. Here, we show that overexpression of AICDA causes more aggressive disease and worse outcome in BCL2-driven murine lymphomas. This phenotype was associated with significantly increased focal inter-tumor and intra-tumor cytosine methylation heterogeneity as compared to control lymphomas, but not with increased mutational burden. AICDA-mediated epigenetic heterogeneity was accompanied by DNA hypomethylation. Reciprocally, we observed that the focal inter-individual and intra-individual cytosine methylation heterogeneity characteristic of normal GC B-cells was lost upon depletion of AICDA. There was significant overlap of AICDA-induced methylation heterogeneity foci in GC B-cells and murine lymphomas. These observations are relevant to human patients, since DLBCLs with high AICDA expression likewise manifest extensive increases in focal inter-patient and intra-patient heterogeneity as compared to DLBCLs with low AICDA expression. Affected regions significantly overlapped with those found in murine AICDA-overexpressing lymphomas. Our results identify AICDA as a novel source of epigenetic plasticity and heterogeneity in B-cell lymphomas with potential significance for other tumors that express cytosine deaminases.

2018-01-19 | GSE95013 | GEO

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

TiSA: TimeSeriesAnalysis – A pipeline for the analysis of longitudinal transcriptomics data

Project description:RNAseq dataset created to evaluate Activation Induced Cytidine Deaminase (AICDA/AID) stimulation cocktails in peripheral blood mononuclear cells (PBMC)

2023-02-13 | GSE213255 | GEO

Differential programming of B cells in Aicda-/- mice [MethylCap-Seq]

Project description:We determined CpG methylation load from GC B cells obtained from both Aicda-/- and Aicda+/+ mice. Examination of methylation load of Aicda-/- and Acida+/+ GC B cells.

2013-06-07 | E-GEOD-47704 | biostudies-arrayexpress

SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B-cell lymphomagenesis

Project description:SETD2 is the sole chromatin modifier responsible for H3K36me3, a histone mark linked to splicing, transcription initiation and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is virtually always heterozygous in diffuse large B-cell lymphomas (DLBCL). Here we show that heterozygous SETD2 deficiency results in germinal center (GC) hyperplasia and accelerated lymphomagenesis. SETD2 haploinsufficient GC B-cells exhibit increased competitive fitness and reduced DNA damage checkpoint activity, resulting in decreased apoptosis. SETD2 haploinsufficient GCB and lymphoma cells featured increased off- and on-target AICDA induced somatic hypermutation (SHM), complex structural variants such as rygma, and increased translocations including those activating MYC. DNA damage was selectively increased on the non-template strand and H3K36me3 loss was associated with greater RNA Pol II processivity and mutational burden, suggesting that SETD2-mediated H3K36me3 is required for proper sensing of cytosine deamination during transcription. Hence, SETD2 haploinsufficiency delineates a novel GC B-cell context specific oncogenic pathway involving defective epigenetic surveillance of AICDA mediated somatic hypermutation induced off target effects on transcribed genes.

2022-04-06 | GSE189867 | GEO

The DNA methylomes of hyper-IgM syndrome type 2 B cells provide insights into the roles of activation-induced deaminase prior to the germinal center reaction

Project description:Inactivating mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although there is evidence both to support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation defects. For genes that undergo demethylation in the transition from naïve to memory B cells but not in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naïve B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports 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 without involvement of its cytosine deaminase activity.

2020-12-31 | GSE134664 | GEO

Naïve B cells vs germina center B cells

Project description:Activation-induced cytidine deaminase (AID) is essential for the generation of antibody memory but also targets oncogenes among others. We investigated the transcriptional regulation of the AID gene, Aicda, in the class switch–inducible CH12F3-2 cells, and found that the Aicda regulation involves derepression by several layers of positive regulatory elements in addition to the 5’ promoter region. The 5’ upstream region contains functional motifs for the response to signaling by cytokines, CD40-ligand, or stimuli that activate NF-κB. The first intron contains functional binding elements for the ubiquitous silencers c-Myb and E2f and for B cell–specific activator Pax5 and E-box-binding proteins. To confirm involvement of these transcription factors in Acida regulation, we examined their expression profile of these factors in naïve and germinal center B cells.

2009-10-27 | GSE18746 | GEO

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

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.

2021-04-13 | GSE172011 | GEO

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