Inhibition of H3K27me3-specific demethylases promotes plasma cell formation

Abstract

Abstract B cell terminal differentiation must be properly regulated to ensure robust humoral immune responses. In additional to the well-established role of key transcription factors, there is a growing interest in the epigenetic regulation of B cell differentiation. However, the epigenetic remodeling that occurs to suppress the B cell and promote the plasma cell fate is still poorly understood. Histone H3 lysine 27 trimethylation (H3K27me3) is a modification associated with a repressive chromatin state and gene silencing. H3K27me3 is established by EZH2 (component of PRC2) and was shown to be essential in the formation and maintenance of germinal centers. In addition, other studies have shown that active removal of silencing marks by H3K27me3-specific demethylases is necessary for T-cell differentiation. To further evaluate the role of H3K27me3 in plasma cell differentiation, we evaluated the effects of pharmacological inhibition of UTX and JMJD3 (H3K27me3-specific demethylases) in B cells stimulated ex vivo with LPS, IL2, and IL5 in the presence of the inhibitor or vehicle control. Our preliminary data suggest that retention of those silencing histone modifications nearly doubles the number of B220+ CD138+ plasma cells after 3-day ex vivo culture as assayed by flow cytometry. We also evaluated viability, gene expression profile, and functionality of the plasma cells treated with or without the inhibitor. Taken together, the collected data provide us with more insight into the role of H3K27me3 dynamics in B cell terminal differentiation.