Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch.
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.
Muto
Akihiko
A
Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Ochiai
Kyoko
K
Kimura
Yoshitaka
Y
Itoh-Nakadai
Ari
A
Calame
Kathryn L
KL
Ikebe
Dai
D
Tashiro
Satoshi
S
Igarashi
Kazuhiko
K
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D017578:Immunoglobulin Class Switching; D007075:Immunoglobulin M / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008954:Models, Biological; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology
C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D007075:Immunoglobulin M; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1