2. Academic Validation
  3. Accelerated plasma-cell differentiation in Bach2-deficient mouse B cells is caused by altered IRF4 functions

Accelerated plasma-cell differentiation in Bach2-deficient mouse B cells is caused by altered IRF4 functions

  • EMBO J. 2024 Apr 11. doi: 10.1038/s44318-024-00077-6.
Kyoko Ochiai 1,  Hiroki Shima 2,  Toru Tamahara 3,  Nao Sugie 2,  Ryo Funayama 4,  Keiko Nakayama 4,  Tomohiro Kurosaki 5 6,  Kazuhiko Igarashi 7 8
Affiliations

Affiliations

  • 1 Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, 980-8575, Japan. [email protected].
  • 2 Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, 980-8575, Japan.
  • 3 Division of Community Oral Health Science, Department of Community Medical Supports, Tohoku Medical Megabank Organization, Tohoku University, Seiryo-machi 2-1, Sendai, 980-8573, Japan.
  • 4 Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, 980-8575, Japan.
  • 5 Laboratory of Lymphocyte Differentiation, Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan.
  • 6 Laboratory for Lymhocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Kanagawa, 230-0045, Japan.
  • 7 Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, 980-8575, Japan. [email protected].
  • 8 Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, 980-8575, Japan. [email protected].
PMID: 38605225 DOI: 10.1038/s44318-024-00077-6
Abstract

Transcription factors BACH2 and IRF4 are both essential for antibody class-switch recombination (CSR) in activated B lymphocytes, while they oppositely regulate the differentiation of plasma cells (PCs). Here, we investigated how BACH2 and IRF4 interact during CSR and plasma-cell differentiation. We found that BACH2 organizes heterochromatin formation of target gene loci in mouse splenic B cells, including targets of IRF4 activation such as Aicda, an inducer of CSR, and Prdm1, a master plasma-cell regulator. Release of these gene loci from heterochromatin in response to B-cell receptor stimulation was coupled to AKT-mTOR pathway activation. In Bach2-deficient B cells, PC genes' activation depended on IRF4 protein accumulation, without an increase in Irf4 mRNA. Mechanistically, a PU.1-IRF4 heterodimer in activated B cells promoted BACH2 function by inducing gene expression of Bach2 and PTEN, a negative regulator of Akt signaling. Elevated Akt activity in Bach2-deficient B cells resulted in IRF4 protein accumulation. Thus, BACH2 and IRF4 mutually modulate the activity of each other, and BACH2 inhibits PC differentiation by both the repression of PC genes and the restriction of IRF4 protein accumulation.

Keywords

Bach2-deficiency; BACH2 Complex; Heterochromatin; IRF4 Protein Accumulation; The PU.1-IRF4 Heterodimer.

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