Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells
Transcription factor Ebf1 regulates differentiation stage-specific signaling, proliferation, and survival of B cells
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DOI：
10.1101/gad.187328.112
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发表时间：
2012-04-01
影响因子：
10.5
通讯作者：
Grosschedl, Rudolf
中科院分区：
文献类型：
--
作者：
Gyoery, Ildiko;Boller, Soeren;Grosschedl, Rudolf
转录因子EBF1是早期B淋巴细胞生成的重要决定因素。为了深入了解EBF1在不同分化阶段的功能，我们有条件地使EBF1失活。我们发现EBF1是前B细胞和外周B细胞亚群，包括B1细胞和边缘区B细胞的增殖、生存和信号传递所必需的。通过v-Abl的转化，可以克服EBF1缺陷的Pro-B细胞的增殖缺陷和多种细胞周期调节因子的表达受损。通过强制表达EBF1靶基因c-Myb或Bclx(L)，可以挽救转化的EBF1(f1/fl)Pro-B细胞的存活缺陷。在成熟的B细胞中，EBF1缺乏通过依赖于B细胞激活因子受体(BAFF-R)和B细胞受体(BCR)的Akt通路干扰信号传导。此外，EBF1对于生发中心的形成和类开关重组都是必需的。对EBF1介导的基因表达和染色质结合的全基因组分析表明，EBF1调节早期和晚期B细胞中常见和不同的基因集。通过调节转录因子和信号网络的重要组成部分，EBF1似乎参与了B淋巴细胞生成的多个阶段的细胞增殖、存活和分化的协调。
The transcription factor Ebf1 is an important determinant of early B lymphopoiesis. To gain insight into the functions of Ebf1 at distinct stages of differentiation, we conditionally inactivated Ebf1. We found that Ebf1 is required for the proliferation, survival, and signaling of pro-B cells and peripheral B-cell subsets, including B1 cells and marginal zone B cells. The proliferation defect of Ebf1-deficient pro-B cells and the impaired expression of multiple cell cycle regulators are overcome by transformation with v-Abl. The survival defect of transformed Ebf1(fl/fl) pro-B cells can be rescued by the forced expression of the Ebf1 targets c-Myb or Bcl-x(L). In mature B cells, Ebf1 deficiency interferes with signaling via the B-cell-activating factor receptor (BAFF-R)- and B-cell receptor (BCR)-dependent Akt pathways. Moreover, Ebf1 is required for germinal center formation and class switch recombination. Genome-wide analyses of Ebf1-mediated gene expression and chromatin binding indicate that Ebf1 regulates both common and distinct sets of genes in early and late stage B cells. By regulating important components of transcription factor and signaling networks, Ebf1 appears to be involved in the coordination of cell proliferation, survival, and differentiation at multiple stages of B lymphopoiesis.