Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells
Plasmacytic transcription factor Blimp-1 is repressed by Bach2 in B cells
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DOI：
10.1074/jbc.m607592200
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发表时间：
2006-12-15
影响因子：
4.8
通讯作者：
Igarashi, Kazuhiko
中科院分区：
文献类型：
--
作者：
Ochiai, Kyoko;Katoh, Yasutake;Igarashi, Kazuhiko
Bach2是一种B细胞特异性转录抑制因子，其在小鼠体内的缺陷会导致免疫球蛋白基因的类开关重组减少和体细胞高度突变减少。Bach2在B细胞中的直接靶基因知之甚少。通过对不同的B细胞和浆细胞系的分析，我们发现Bach2和浆细胞分化的主要调节因子Blimp-1(B淋巴细胞诱导成熟蛋白1)的表达模式是相互排斥的。Blimp-1基因的报告基因Prdm1在B细胞中的过表达抑制了Bach2的表达。在凝胶迁移率改变分析中，Bach2/MafK的异源二聚体与Maf识别元件结合，位于Prdm1启动子的上游。染色质免疫沉淀实验证实B细胞MafK与Prdm1Maf识别元件结合。从BAL17B细胞中纯化MafK时，很大一部分MafK与Bach2以异源二聚体形式存在，没有明显的MafK同源二聚体形成。这些结果有力地表明，Bach2在浆细胞分化之前抑制了B细胞中Blimp-1和MafK的表达。因此，在BAL17细胞中，用短发夹状RNA敲除Bach2mRNA导致表面IgM交联刺激B细胞受体后Prdm1表达水平升高。在脂多糖刺激下，在原代Bach2缺陷B细胞中，Prdm1的诱导比野生型对照B细胞更强劲和更快。因此，B细胞中Prdm1的调节涉及到Bach2的抑制，这种抑制可能在终末浆细胞分化时被取消。
Bach2 is a B cell-specific transcription repressor whose deficiency in mice causes a reduced class switch recombination and a reduced somatic hypermutation of immunoglobulin genes. Little is known about the direct target genes of Bach2 in B cells. By analyzing various B cell and plasma cell lines, we showed that the expression patterns of Bach2 and Blimp-1 (B lymphocyte-induced maturation protein 1), a master regulator of plasma cell differentiation, are mutually exclusive. The reporter gene of the Blimp-1 gene (Prdm1) was repressed by the overexpression of Bach2 in B cell lines. The heterodimer of Bach2/MafK bound to the Maf recognition element located upstream of the Prdm1 promoter in an electrophoretic mobility shift assay. The binding of MafK in B cells to the Prdm1 Maf recognition element was confirmed by chromatin immunoprecipitation assays. When MafK was purified from the BAL17 B cell line, a significant portion of it was present as a heterodimer with Bach2, with no apparent formation of MafK homodimer. These results strongly suggest that Bach2 represses the expression of Blimp-1 together with MafK in B cells prior to plasma cell differentiation. Accordingly, the knockdown of Bach2 mRNA using short hairpin RNA in BAL17 cells resulted in higher levels of Prdm1 expression after the stimulation of B cell receptor by surface IgM cross-linking. Induction of Prdm1 was more robust and faster in primary Bach2-deficient B cells than in wild-type control B cells upon lipopolysaccharide stimulation. Therefore, the Prdm1 regulation in B cells involves the repression by Bach2, which may be cancelled upon terminal plasma cell differentiation.