Single cell clonal analysis identifies an AID-dependent pathway of plasma cell differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA784455 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17063343_1.fastq.gz | Fastqsanger.gz | |||
| SRR17063343_2.fastq.gz | Fastqsanger.gz | |||
| SRR17063344_1.fastq.gz | Fastqsanger.gz | |||
| SRR17063344_2.fastq.gz | Fastqsanger.gz | |||
| SRR17063345_1.fastq.gz | Fastqsanger.gz |
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Project description:Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody secreting plasma cells. Here we have addressed the role of Activation Induced Deaminase (AID), which initiates somatic hypermutation and class switch recombination, in the terminal differentiation of GC B cells. By combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells, we have identified a novel subset of late prePB cells (L-prePB), which shares the strongest clonal relationships with PBs. Mice lacking AID have various alterations in the size and expression profiles of transcriptional clusters. We find that AID deficiency leads to a reduced proportion of L-prePB cells and severely impairs transitions between the L-prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state.
2022-09-06 | GSE189775 | GEO
Project description:Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody-secreting plasma cells. Here, we have addressed the role of activation-induced deaminase (AID), which initiates somatic hypermutation and class switch recombination, in the terminal differentiation of GC B cells. By combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells, we have identified a novel subset of late-prePB cells (L-prePB), which shares the strongest clonal relationships with plasmablasts (PBs). Mice lacking AID have various alterations in the size and expression profiles of transcriptional clusters. We find that AID deficiency leads to a reduced proportion of L-prePB cells and severely impairs transitions between the L-prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state.
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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:AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5’ single cell RNA sequencing on 9 newly diagnosed, treatment naive AL amyloidosis patients and 8 healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of CD16 monocytes and subsets of CD4+ T cells in AL amyloidosis patients. We detected significant transcriptional changes broadly occurring among immune cells with increased interferon α and γ response and decreased TNF-α signaling. T and B cell receptor profiling revealed no overt clonal expansion of B or T cells in AL amyloidosis patients. However, we noted a disproportionate expansion of a distinct population of non-malignant plasma cells in AL amyloidosis patients. Finally, clonal AL amyloidosis plasma cells were identified based on their unique VDJ rearrangement and they showed increased expression of genes involved in proteostasis and antigen processing when compared to autologous, polyclonal plasma cells. Inter-patient transcriptional heterogeneity was evident, with transcriptional states reflective of common genomic translocations easily identifiable. Overall, this study defines the transcriptional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment, identifying transcriptional signatures that serve as candidates in early diagnosis in larger studies, and potential molecular targets for therapy.
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Project description:Activation-Induced Cytidine Deaminase (AID) is required for somatic hypermutation and immunoglobulin (Ig) class switch recombination in germinal center B lymphocytes. Occasionally, AID targets non-Ig genes, thereby contributing to B cell lymphomagenesis. We recently reported aberrant expression of AID in BCR-ABL1-driven acute lymphoblastic leukemia (ALL). To elucidate the biological significance of aberrant AID expression, we studied loss of AID function in a murine model of BCR-ABL1 ALL. Mice transplanted with BCR-ABL1-transduced AID-/- bone marrow had prolonged survival as compared to mice transplanted with leukemia cells generated from AID+/+ bone marrow. Consistent with a causative role of AID in genetic instability, AID-/- leukemia had a decreased frequency of amplifications, deletions and a lower frequency of mutations in non-Ig genes including Pax5 and Rhoh as compared to AID+/+ leukemias. AID-/- and AID+/+ ALL cells showed a markedly distinct gene expression pattern as determined by principle component analysis, with 2,365 genes differentially expressed. In contrast to AID+/+ leukemia, AID-/- ALL cells failed to downregulate a number of tumor suppressor genes such as Rhoh, Cdkn1a (p21), and Blnk (SLP65). We conclude that AID accelerates clonal evolution in BCR-ABL1 ALL by enhancing genetic instability, aberrant somatic hypermutation, and by transcriptional inactivation of tumor suppressor genes. Experiment Overall Design: We used microarrays to detect differences in gene expression profiles between AID expressing leukemia and AID deficient leukemia
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Project description:The antibody gene mutator AID promiscuously damages oncogenes and B cell identity genes leading to chromosomal translocations and tumorigenesis. Why non-immunoglobulin loci are susceptible to AID activity is unknown. Here we study AID-mediated lesions in the context of nuclear architecture and the B cell regulome. We show that AID targets are not randomly distributed across the genome, but are predominantly clustered within super-enhancers. Unexpectedly, in these domains AID deaminates highly active promoters and eRNA+ enhancers interconnected in some instances over megabases of linear chromatin. Using genome editing we demonstrate that 3D-linked targets cooperate to recruit AID-mediated breaks. Furthermore, a comparison of hypermutation in mouse B cells, AID-induced kataegis in human lymphomas, and translocations in MEFs reveals that AID damages different genes in different cell types. Yet, in all cases, the targets are predominantly associated with topological complex, highly transcribed super-enhancers, demonstrating that these compartments are key mediators of AID recruitment. Examination of AID activity in human cells via Single Nucleotide Variant discovery in H3K4me3 ChIP-seq data from 26 MSH2-/-; AIDtg; UGItg, 18 AICDA-/- and 2 unmodified RAMOS clonal populations. Examination of PolII mediated long-range interactions via Chia-PET of RAMOS cells (2 sample). Identification of super-enhancers from H3K27Ac ChIP-Seq data from activated B cells (3 replicates and 1 input control) and RAMOS cells (1 sample and 1 input control), 2 preparations of naive and 2 of germinal center (GC) B cells from human tonsilectomy samples. Mapping of regulatory elements in RAMOS based on H3K4me1 (1 sample) and Nipbl (2 replicates) ChIP-Seq. RNA expression analyses of activated B cells from 3 WT and 3 Il4raU/U mice and RAMOS cells (3 replicates). Mapping of long-range interactions by 4C in activated B cells from a WT and an Il4raU/U mouse with the IL4ra and Il21r locus, respectively, as a viewpoint. Mapping of Super-Enhancers in activated B cells from Il4raU/U and WT control mice (2 samples).
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Project description:Clonal evolution of pre-malignant B-cells in the absence of AID
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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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