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

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.

Epigenetic regulation of B cell fate and function during an immune response

“…Both demethylation and de novo methylation has been found to be important in plasma cell differentiation . Activation‐induced hypomethylation is a common and critical mechanistic step for differentiation into all downstream B cell subsets (ie, germinal center, plasma cell and memory B cells).…”

“…Activation‐induced hypomethylation is a common and critical mechanistic step for differentiation into all downstream B cell subsets (ie, germinal center, plasma cell and memory B cells). In contrast, de novo methyltransferases are specifically required for appropriate plasma cell gene expression . Active demethylation at plasma cell genes, particularly enhancers, is important for plasmablast commitment during cell cycle .…”

“…The small, but important, increase in de novo methylation in plasma cells suggested that de novo methylation may also be occurring during B cell differentiation . To investigate, Barwick et al conditionally deleted the de novo DNA methyltransferases DNMT3A and DNMT3B in B cells. While B cell development appeared normal in these mice, there was an increase in the size of germinal centers, antibody titres and bone marrow‐resident plasma cells .…”

Multiple myeloma immunoglobulin λ translocations portend poor prognosis

“…The data herein provide motivation for determining the efficacy of such transcriptional regulators in the context of t(IgL) myeloma, but also a rationale for the better understanding of cis-regulatory factors affecting transcription at translocated loci. This daunting task not only requires an understanding of the combinatorial effects of the trans-acting molecular machinery, but also a cartography of the chromatin structure, epigenetic mechanisms known to influence plasma cell fate 43,44 , and enhancer function in the context of translocation breakpoints and micro-environmental ques. Such results will ultimately need to be placed in the context of multicellular organisms and bone marrow micro-environmental ques to help identify drug targets with high specificity for the transcriptional program and genetic architecture of myeloma.…”

A Mixture of Functional Complex Extracts from Lycium barbarum and Grape Seed Enhances Immunity Synergistically In Vitro and In Vivo

“…LPS extracted from different bacteria has different sugar chain length and structure of the polysaccharide so that the sensitivity to the same cell is different. Chosen from different kinds of commercial LPS, LPS from Escherichia coli O111:B4 is one of the most widely used that has strong effects on stimulating B cells (Barwick et al., ). The plate was centrifuged at 300 × g for 5 min and the supernatant was removed.…”