Inhibition of H3K27me3 Demethylases Promotes Plasmablast Formation

• Type of Material: Article
• Authors: Anna K Kania, Emory University; Muyao Guo, Emory University; Christopher Scharer, Emory University; Jeremy Boss, Emory University
• Language: English
• Date: 2021-12-01
• Publisher: The American Association of Immunologists, Inc
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.4049/immunohorizons.2000087
• Title of Journal or Parent Work: ImmunoHorizons
• Volume: 5
• Issue: 12
• Start Page: 918
• End Page: 930
• Grant/Funding Information: This work was supported by National Institute of Health grants: RO1 AI123733 and P01 AI125180 to J.M.B, T32 GM0008490 to A.K.K.
• Keywords: Pyrimidines; Animals; Mice, Inbred C57BL; Mice; Plasma Cells; Signal Transduction; Jumonji Domain-Containing Histone Demethylases; Cell Differentiation; Histone Demethylases; Benzazepines

Abstract

B cell differentiation into Ab-secreting plasma cells requires transcriptional, metabolic, and epigenetic remodeling. Histone H3 lysine 27 trimethylation (H3K27me3), a histone modification associated with gene silencing, is dynamically regulated during B cell differentiation. Although several studies have focused on mechanisms involving the gain of this modification in plasmablasts (PB), the role of active demethylation of H3K27me3 by ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) and Jumonji domain-containing protein 3 (JMDJ3) during B cell differentiation has not been examined. In this study, this process was assessed using a pharmacological inhibitor of UTX and JMJD3, GSK-J4. Treatment of ex vivo stimulated mouse B cells with GSK-J4 led to an increase in PB frequency without affecting the ability of the newly formed PB to secrete Abs. Consistent with the role of UTX and JMJD3 in promoting gene expression, the majority of differentially expressed were downregulated upon GSK-J4 treatment. GSKJ4–treated cells downregulated genes associated with signaling and P53 pathways. Inhibitor treated cells upregulated genes associated with cell cycle and proliferation, which correlated with an increase in actively proliferating cells. Unexpectedly, a majority of the downregulated transcripts corresponded to genes that in the wild-type setting were genes that gain H3K27me3 and downregulated in PB. Together, our results show that UTX and JMDJ3 are required to restrain B cell differentiation and suggest that they function as a rheostat for H3K27me3 to control this process.