H3K27me3 demethylases restrict the magnitude of PC formation

Abstract Robust differentiation of naïve B cell into antibody secreting plasma cells (PC) in response to foreign antigens is a cornerstone of the humoral immune response. PC formation is highly regulated and requires substantial epigenetic remodeling, including redistribution of histone modification H3 lysine 27 trimethylation (H3K27me3), which is associated with a repressive chromatin state and gene silencing. However, little is known about the role of the two demethylases, UTX and JMDJ3, that remove H3K27me3 in B cells. To examine whether these enzymes module PC formation, we generated mice with B cell specific deletion of UTX and JMDJ3 (dKO; Utxfl/flJmjd3fl/fl Cd19Cre/+). Stimulation of B cells with T cell independent antigens, LPS or NP-Ficoll, led to a significant increase in PC in dKO mice compared to CreCtrl mice (Cd19Cre/+). This phenotype was attributed to enhanced proliferation and differentiation of marginal zone (MZ), but not follicular B cells (FoB). dKO PC upregulated genes associated with oxidative phosphorylation metabolism and exhibited higher spare respiratory capacity. Furthermore, deletion of UTX and JMJD3 led to significant redistribution of accessible chromatin and H3K27me3. Regions with reduced chromatin accessibility in dKO PC were enriched for transcription factor motifs of known PC repressors suggesting a potential mode of regulation. Additionally, we demonstrated that UTX is the primary H3K27me3 demethylase regulating B cell differentiation and evaluated whether its demethylase activity is required to augment PC formation. Taken together, H3K27me3 demethylases are critical epigenetic regulators necessary restrain B cell differentiation.