Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch

Akihiko Muto, Kyoko Ochiai, Yoshitaka Kimura, Ari Itoh-Nakadai, Kathryn L. Calame, Dai Ikebe, Satoshi Tashiro, Kazuhiko Igarashi

Research output: Contribution to journalArticle

130 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4048-4061
Number of pages14
JournalEMBO Journal
Volume29
Issue number23
DOIs
Publication statusPublished - 2010 Dec 1

Keywords

  • AID
  • B cell
  • Bach2
  • Blimp-1
  • gene regulatory network

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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