B cell activation and plasma cell differentiation are inhibited by de novo DNA methylation

• DOI: 10.1038/s41467-018-04234-4
• Publication Date: 2018-05-09T09:33:07Z
• Authors: Benjamin G. Barwick; Christopher D. Sc...; Ryan J. Martinez; Madeline J. Price; Alexander N. Wein; Robert R. Haines; Alexander P. R. B...; Jacob E. Kohlmeier; Jeremy M. Boss
• Keywords: Male; DNA Methyltransferase 3B; 0301 basic medicine; B-Lymphocytes; Science; Q; Plasma Cells; Cell Differentiation; DNA Methylation; Lymphocyte Activation; Article; Chromatin; DNA Methyltransferase 3A; Mice; 03 medical and health sciences; Animals; Female; DNA (Cytosine-5-)-Methyltransferases; Gene Deletion

AbstractB cells provide humoral immunity by differentiating into antibody-secreting plasma cells, a process that requires cellular division and is linked to DNA hypomethylation. Conversely, little is known about how de novo deposition of DNA methylation affects B cell fate and function. Here we show that genetic deletion of the de novo DNA methyltransferases Dnmt3a and Dnmt3b (Dnmt3-deficient) in mouse B cells results in normal B cell development and maturation, but increased cell activation and expansion of the germinal center B cell and plasma cell populations upon immunization. Gene expression is mostly unaltered in naive and germinal center B cells, but dysregulated in Dnmt3-deficient plasma cells. Differences in gene expression are proximal to Dnmt3-dependent DNA methylation and chromatin changes, both of which coincide with E2A and PU.1-IRF composite-binding motifs. Thus, de novo DNA methylation limits B cell activation, represses the plasma cell chromatin state, and regulates plasma cell differentiation.