H3k27me3 Demethylases Are Important Epigenetic Regulators Of B Cell Differentiation

Abstract The humoral immune response relies on robust differentiation of naïve B cells into antibody secreting plasma cells (PC) in response to foreign, but not self-antigens. To ensure proper immune responses, B cell differentiation is regulated through processes that remodel the epigenome. The histone modification H3 lysine 27 trimethylation (H3K27me3) is associated with a repressive chromatin state and gene silencing. This histone modification is deposited by EZH2, which has been shown to regulate all stages of B cell differentiation leading to PC. However, a role for the two demethylases UTX and JMJD3 that remove H3K27me3 in B cells is still to be elucidated. To determine how these enzymes modulate B cell differentiation, we crossed Utxfl/flJmjd3fl/flmice onto the Cd19Cre/+background (dKO mice). Stimulation of Cd19Cre/+(CreCtrl) and dKO mice with the T cell independent antigen LPS led to a significant increase in PC in dKO mice. This phenotype was attributed to enhanced differentiation of marginal zone (MZ), but not follicular B cells (FoB). UTX- and JMJD3-deficient PC unregulated genes associated with oxidative phosphorylation metabolism and resulted in a significantly higher spare respiratory capacity. In response to infection with influenza virus, we observed a significant increase in GC B cells in UTX- and JMJD3-deficient mice. Taken together, our data place H3K27me3 demethylases as critical epigenetic regulators that restrict B cell responses to T cell dependent and independent stimuli.