A pinboard by
Andrea Di Pietro

Postdoctoral Fellow, Monash University


Polycomb group proteins are crucial in the epigenetic control of germinal centers

Humoral immunity against pathogens relies upon the germinal center (GC), which coordinates the production of high-affinity antibody-secreting cells and the formation of long-lasting memory B cells. The GC developmental program is finely regulated by epigenetic modifiers. Among these, Polycomb repressive complexes (PRCs) work in tandem to exert their enzymatic activity in maintaining the silenced state of target genes through the deposition of methyl or ubiquitin groups on histone proteins. We hypothesised that these complexes regulate niche-specific GC processes. We are therefore investigating the roles of PRC1/2 in B cell differentiation during immune responses to infections. We explored the activity of the embryonic ectoderm development (EED) protein, as a ​subunit of the PRC2, and the E3-ubiquitin ligase B lymphoma Mo-MLV insertion region 1 homolog (BMi1) in the PRC1 during GC reactions. Our results revealed a crucial role for these proteins in B cell differentiation and antibody class-switching in vivo. Unveiling the epigenetic regulators required for the establishment of a protective long-term B cell response during acute infection, and how this may be dysregulated in chronic infection, may open up new avenues for therapeutic intervention.


Regulation of germinal center responses and B-cell memory by the chromatin modifier MOZ.

Abstract: Memory B cells and long-lived bone marrow-resident plasma cells maintain humoral immunity. Little is known about the intrinsic mechanisms that are essential for forming memory B cells or endowing them with the ability to rapidly differentiate upon reexposure while maintaining the population over time. Histone modifications have been shown to regulate lymphocyte development, but their role in regulating differentiation and maintenance of B-cell subsets during an immune response is unclear. Using stage-specific deletion of monocytic leukemia zinc finger protein (MOZ), a histone acetyltransferase, we demonstrate that mutation of this chromatin modifier alters fate decisions in both primary and secondary responses. In the absence of MOZ, germinal center B cells were significantly impaired in their ability to generate dark zone centroblasts, with a concomitant decrease in both cell-cycle progression and BCL-6 expression. In contrast, there was increased differentiation to IgM and low-affinity IgG1(+) memory B cells. The lack of MOZ affected the functional outcome of humoral immune responses, with an increase in secondary germinal centers and a corresponding decrease in secondary high-affinity antibody-secreting cell formation. Therefore, these data provide strong evidence that manipulating epigenetic modifiers can regulate fate decisions during humoral responses, and thus could be targeted for therapeutic intervention.

Pub.: 01 Jul '14, Pinned: 28 Jul '17

Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis.

Abstract: Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many 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 is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte-induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases.

Pub.: 10 Nov '13, Pinned: 28 Jul '17