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

• Type of Material: Article
• Authors: Benjamin G. Barwick, Emory University; Christopher Scharer, Emory University; Ryan J. Martinez, Emory University; Madeline J. Price, Emory University; Alexander N. Wein, Emory University; Robert R. Haines, Emory University; Alexander P. R. Bally, Emory University; Jacob Kohlmeier, Emory University; Jeremy Boss, Emory University
• Language: English
• Date: 2018-05-15
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-04234-4
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 1900
• End Page: 1900
• Grant/Funding Information: B.G.B. was supported by NIH grants T32 GM008490, F31 AI112261, and by a Postdoctoral fellowship, PF-17-109-01, from the American Cancer Society; A.P.R.B. by NIH T32 AI007610; R.J.M. by NIH F31 NS086130; J.E.K. by NIH R01 HL122559; and J.M.B. by NIH RO1 AI123733, U19 AI110483, and 5PO1 AI125180.; This study was supported in part by the Emory Integrated Genomics Core Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30 CA138292.
• Keywords: TRANSCRIPTION; RESOLUTION; DNMT3A; TERMINAL DIFFERENTIATION; HEMATOPOIETIC STEM; Science & Technology; METHYLOME; EXPRESSION; Science & Technology - Other Topics; METHYLTRANSFERASE 1; Multidisciplinary Sciences; GENOME; REGULATORY ELEMENTS
• Research Categories: Biology, Microbiology; Health Sciences, Medicine and Surgery; Health Sciences, Immunology

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.