Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch
Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch
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DOI：
10.1038/emboj.2010.257
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发表时间：
2010-12-01
期刊：
影响因子：
11.4
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
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作者：
Muto, Akihiko;Ochiai, Kyoko;Igarashi, Kazuhiko
两个转录因子Pax5和Blimp-1形成一个双负环的基因调控网络（GRN），作为二进制开关决定b细胞（Pax5高）或浆细胞（Blimp-1高）的状态。然而，目前尚不清楚这种b细胞GRN如何记录类转换DNA重组（CSR），这是发生在浆细胞终端分化之前的事件。在缺乏编码CSR所需转录因子Bach2的情况下，小鼠脾B细胞比野生型细胞更频繁和快速地表达Blimp-1并分化为IgM浆细胞。Blimp-1基因在Bach2(-/-) B细胞中的缺失足以恢复CSR。这些数据与GRN的数学建模表明，Bach2在Blimp-1诱导中实现了时间延迟，从而抑制了浆细胞分化，促进了CSR （delay - driven Diversity model for CSR）。Blimp-1消融并不能挽救Bach2（-/-）小鼠成熟b细胞数量的减少，表明Bach2通过Blimp-1依赖性和非依赖性grn调节b细胞的分化和功能。EMBO杂志，2010,29,4048-4061。doi: 10.1038 / emboj.2010.257;2010年10月15日在线发布
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. The EMBO Journal (2010) 29, 4048-4061. doi:10.1038/emboj.2010.257; Published online 15 October 2010