Abstract
B 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.
Highlights
B cells provide humoral immunity by differentiating into antibody-secreting plasma cells, a process that requires cellular division and is linked to DNA hypomethylation
Data far suggest that B cells undergo extensive and targeted DNA hypomethylation upon activation, but it is not known if de novo DNA methylation is important for B cell fate and function
Deposition of de novo DNA methylation by Dnmt3a and Dnmt3b is required for mammalian development[25] and when deleted in hematopoietic stem cells restricts B cell development[26,27], but how it contributes to the molecular programming, differentiation, and function of mature B cells is not well understood
Summary
B cells provide humoral immunity by differentiating into antibody-secreting plasma cells, a process that requires cellular division and is linked to DNA hypomethylation. How gene expression programs are both remodeled and propagated across the many rounds of cellular division during B cell differentiation is not well understood Epigenetic mechanisms, such as DNA methylation, have the potential to control gene expression and cell identity through mitosis[7]. Deposition of de novo DNA methylation by Dnmt3a and Dnmt3b is required for mammalian development[25] and when deleted in hematopoietic stem cells restricts B cell development[26,27], but how it contributes to the molecular programming, differentiation, and function of mature B cells is not well understood. Dnmt3-deficient mice have enlarged germinal center and plasma cell responses by a cell autonomous mechanism coupled to gene dysregulation, a failure to gain de novo DNA methylation, and repress the chromatin state in bone marrow plasma cells. Dnmt3-dependent DNA methylation restricts B cell activation and plasma cell differentiation
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