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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.

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