Premium
Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch
Author(s) -
Muto Akihiko,
Ochiai Kyoko,
Kimura Yoshitaka,
ItohNakadai Ari,
Calame Kathryn L,
Ikebe Dai,
Tashiro Satoshi,
Igarashi Kazuhiko
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2010.257
Subject(s) - biology , b cell , immunoglobulin class switching , transcription factor , pax5 , plasma cell , gene , microbiology and biotechnology , cellular differentiation , antibody , genetics
Two transcription factors, Pax5 and Blimp‐1, form a gene regulatory network (GRN) with a double‐negative loop, which defines either B‐cell (Pax5 high) or plasma cell (Blimp‐1 high) status as a binary switch. However, it is unclear how this B‐cell GRN registers class switch DNA recombination (CSR), an event that takes place before the terminal differentiation to plasma cells. In the absence of Bach2 encoding a transcription factor required for CSR, mouse splenic B cells more frequently and rapidly expressed Blimp‐1 and differentiated to IgM plasma cells as compared with wild‐type cells. Genetic loss of Blimp‐1 in Bach2 −/− B cells was sufficient to restore CSR. These data with mathematical modelling of the GRN indicate that Bach2 achieves a time delay in Blimp‐1 induction, which inhibits plasma cell differentiation and promotes CSR (Delay‐Driven Diversity model for CSR). Reduction in mature B‐cell numbers in Bach2 −/− mice was not rescued by Blimp‐1 ablation, indicating that Bach2 regulates B‐cell differentiation and function through Blimp‐1‐dependent and ‐independent GRNs.