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

被引:93
作者
Barwick, Benjamin G. [1 ,2 ]
Scharer, Christopher D. [1 ]
Martinez, Ryan J. [1 ,3 ]
Price, Madeline J. [1 ]
Wein, Alexander N. [1 ]
Haines, Robert R. [1 ]
Bally, Alexander P. R. [1 ,4 ]
Kohlmeier, Jacob E. [1 ]
Boss, Jeremy M. [1 ]
机构
[1] Emory Univ, Sch Med, Dept Microbiol & Immunol, 1510 Clifton Rd,Rm 3001, Atlanta, GA 30322 USA
[2] Emory Univ, Dept Hematol & Med Oncol, Sch Med, 1701 Uppergate Dr,WCI 4060 C, Atlanta, GA 30322 USA
[3] Emory Univ, Sch Med, Dept Med, 1648 Pierce Dr NE, Atlanta, GA 30307 USA
[4] Emory Univ, Sch Med, Dept Microbiol & Immunol, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd NE,Suite 3052, Atlanta, GA 30329 USA
关键词
METHYLTRANSFERASE; 1; HEMATOPOIETIC STEM; TERMINAL DIFFERENTIATION; REGULATORY ELEMENTS; DNMT3A; METHYLOME; TRANSCRIPTION; RESOLUTION; EXPRESSION; LINEAGE;
D O I
10.1038/s41467-018-04234-4
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:14
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