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Genome-wide maps of chromatin state in Germinal Center B cells.

ABSTRACT: Protection against deadly pathogens requires the production of high-affinity antibodies by B cells. High-affinity antibody-forming cells are generated in germinal centers (GC) as a result of a developmental program that is commonly altered in B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions including lymphomas. The Histone H3 lysine-27 methyltransferase Enhancer of Zeste homolog 2 (EZH2) is highly expressed in GC B cells and often constitutively activated in GC-derived Non-Hodgkin lymphomas (NHL), but its function in these cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells causes a profound impairment in GC responses, memory B cell formation and humoral immunity. Mechanistically, Ezh2 protected GC B cells against AID mutagenesis, facilitated cell-cycle progression independent of p16INK4a repression and silenced plasma cell determinants Blimp1 and Irf4. Likewise, EZH2 inhibition in GC-derived NHL cells induced tumor suppressor BLIMP1, which impaired tumor growth. In conclusion, in GC B cells Ezh2 sustains AID function and prevents terminal differentiation to allow antibody diversification and affinity maturation. Dysregulation of such mechanisms may facilitate lymphomagenesis and identifies EZH2 as possible therapeutic target in NHL and other GC-derived B cell diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE50912 | GEO | 2013/12/11

SECONDARY ACCESSION(S): PRJNA219348

REPOSITORIES: GEO

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Genome-wide maps of chromatin state in Germinal Center B cells.

Project description:Protection against deadly pathogens requires the production of high-affinity antibodies by B cells. High-affinity antibody-forming cells are generated in germinal centers (GC) as a result of a developmental program that is commonly altered in B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions including lymphomas. The Histone H3 lysine-27 methyltransferase Enhancer of Zeste homolog 2 (EZH2) is highly expressed in GC B cells and often constitutively activated in GC-derived Non-Hodgkin lymphomas (NHL), but its function in these cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells causes a profound impairment in GC responses, memory B cell formation and humoral immunity. Mechanistically, Ezh2 protected GC B cells against AID mutagenesis, facilitated cell-cycle progression independent of p16INK4a repression and silenced plasma cell determinants Blimp1 and Irf4. Likewise, EZH2 inhibition in GC-derived NHL cells induced tumor suppressor BLIMP1, which impaired tumor growth. In conclusion, in GC B cells Ezh2 sustains AID function and prevents terminal differentiation to allow antibody diversification and affinity maturation. Dysregulation of such mechanisms may facilitate lymphomagenesis and identifies EZH2 as possible therapeutic target in NHL and other GC-derived B cell diseases. In this study, two independent primary samples of splenic GC B cells from C5/BL/6J mice were subjected to H3K27me3 and H3K4me3 ChIP-sequencing. A totale of 6 samples, including input samples, were subjected to ultra-deep sequencing.

2013-12-11 | E-GEOD-50912 | biostudies-arrayexpress

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

Mapping of WT FOXO1 and M1L FOXO1 binding sites in SUDHL4 cells

Project description:The transcription factor FOXO1 directs germinal center (GC) polarity and supports affinity maturation by silencing immune activation programs in GC B cells. Recurrent somatic mutations in GC-derived B cell non-Hodgkin lymphomas (B-NHL) often target and reportedly activate FOXO1 by preventing its negative regulation by PI3K. Herein, using ad hoc mouse models, engineered cell lines and primary tumor specimens, we show instead that FOXO1 mutant proteins display altered transcriptional activities suggestive of partial loss-of-function. These defects drive simultaneous hyperactivation of signaling pathways (Stress Activated Protein Kinase -SAPK/JNK, Phosphoinositide 3-kinase -PI3K/AKT) and gene expression programs typically activated in GC B cells upon positive selection. Such changes confer mutant B cells with competitive advantages in response to key immune signals, leading to abnormal amplification of GC responses. Evidence of these FOXO1 ‘mutant’ gene programs can be found in a fraction of human B-NHL and predict clinical outcome, thus implying the frequent co-option of positive selection programs during GC-derived B-NHL pathogenesis.

2021-07-30 | GSE143774 | GEO

Transcriptional profiling of SUDHL4 cells edited by CRISPR-cas9 to induce point mutations in the FOXO1 locus

2021-07-30 | GSE143773 | GEO

Transcriptional profiling of SUDHL4 cells stimulated with megaCD40L and IgM/G for 24 hours

2021-07-30 | GSE143772 | GEO

EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation

Project description:The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting. RNA sequencing and H3K27me3 ChIP sequencing of human DLBCL cell lines and murine BCL1 cell line. RNA sequencing, H3K27me3 and H3K4me3 ChIP sequencing of B cells from de-identified human tonsills.

2013-05-13 | E-GEOD-45982 | biostudies-arrayexpress

EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation

2013-05-13 | GSE45982 | 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

Dynamic changes in E protein activity orchestrate germinal center and plasma cell development [ChIP-Seq]

Project description:Humoral immunity requires the generation of high-affinity antibodies, which involves the generation of germinal centres (GC) promoting class switch and affinity maturation of antigen-specific B cells, and the differentiation of long-lived plasma cells. This multi-layered process is tightly controlled by the activity of a transcriptional network including Bcl6, essential for the development of GC, and Blimp1, required for the differentiation of plasma cells. Here, we reveal an additional layer of complexity by demonstrating that dynamic changes in E-protein activity mediated by Id3 govern both GC and plasma cell differentiation. We show that down-regulation of Id3 expression in B cells in essential for releasing E2A and E2-2, the combined activity of which is required for both GC B cell and plasma cell differentiation. We demonstrate that this pathway controls the expression of multiple key factors required for antigen-induced B cell differentiation, including Blimp1, Xbp1, Mef2b and CXCR4 and is therefore critical for establishing the transcriptional network that controls GC B cell and plasma cell differentiation. Genome binding of transcription factor E2A

2016-05-13 | E-GEOD-72828 | biostudies-arrayexpress

Dynamic changes in E protein activity orchestrate germinal center and plasma cell development [RNA-Seq]

2016-05-13 | E-GEOD-72831 | biostudies-arrayexpress

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