Bach2 promotes B cell receptor–induced proliferation of b lymphocytes and represses cyclin-dependent kinase inhibitors

Yuichi Miura, Mizuho Morooka, Nicolas Sax, Rahul Roychoudhuri, Ari Itoh-Nakadai, Andrey Brydun, Ryo Funayama, Keiko Nakayama, Susumu Satomi, Mitsuyo Matsumoto, Kazuhiko Igarashi, Akihiko Muto

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

BTB and CNC homology 2 (Bach2) is a transcriptional repressor that is required for the formation of the germinal center (GC) and reactions, including class switch recombination and somatic hypermutation of Ig genes in B cells, within the GC. Although BCR-induced proliferation is essential for GC reactions, the function of Bach2 in regulating B cell proliferation has not been elucidated. In this study, we demonstrate that Bach2 is required to sustain high levels of B cell proliferation in response to BCR signaling. Following BCR engagement in vitro, B cells from Bach2-deficient (Bach2 2 / 2 ) mice showed lower incorporation of BrdU and reduced cell cycle progression compared with wild-type cells. Bach2 2 / 2 B cells also underwent increased apoptosis, as evidenced by an elevated frequency of sub-G 1 cells and early apoptotic cells. Transcriptome analysis of BCR-engaged B cells from Bach2 2 / 2 mice revealed reduced expression of the antiapoptotic gene Bcl2l1 encoding Bcl-x L and elevated expression of cyclin-dependent kinase inhibitor (CKI) family genes, including Cdkn1a, Cdkn2a, and Cdkn2b. Reconstitution of Bcl-x L expression partially rescued the proliferation defect of Bach2 2 / 2 B cells. Chromatin immunoprecipitation experiments showed that Bach2 bound to the CKI family genes, indicating that these genes are direct repression targets of Bach2. These findings identify Bach2 as a requisite factor for sustaining high levels of BCR-induced proliferation, survival, and cell cycle progression, and it promotes expression of Bcl-x L and repression of CKI genes. BCR-induced proliferation defects may contribute to the impaired GC formation observed in Bach2 2 / 2 mice.

Original languageEnglish
Pages (from-to)2882-2893
Number of pages12
JournalJournal of Immunology
Volume200
Issue number8
DOIs
Publication statusPublished - 2018 Apr 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Bach2 promotes B cell receptor–induced proliferation of b lymphocytes and represses cyclin-dependent kinase inhibitors'. Together they form a unique fingerprint.

  • Cite this