Roessler Stephanie, Györy Ildiko, Imhof Sascha, Spivakov Mikhail, Williams Ruth R, Busslinger Meinrad, Fisher Amanda G, Grosschedl Rudolf
Max Planck Institute of Immunobiology, Department of Cellular and Molecular Immunology, 79108 Freiburg, Germany.
Mol Cell Biol. 2007 Jan;27(2):579-94. doi: 10.1128/MCB.01192-06. Epub 2006 Nov 13.
Early differentiation of B lymphocytes requires the function of multiple transcription factors that regulate the specification and commitment of the lineage. Loss- and gain-of-function experiments have provided important insight into the transcriptional control of B lymphopoiesis, whereby E2A was suggested to act upstream of EBF1 and Pax5 downstream of EBF1. However, this simple hierarchy cannot account for all observations, and our understanding of a presumed regulatory network, in which transcription factors and signaling pathways operate, is limited. Here, we show that the expression of the Ebf1 gene involves two promoters that are differentially regulated and generate distinct protein isoforms. We find that interleukin-7 signaling, E2A, and EBF1 activate the distal Ebf1 promoter, whereas Pax5, together with Ets1 and Pu.1, regulates the stronger proximal promoter. In the absence of Pax5, the function of the proximal Ebf1 promoter and accumulation of EBF1 protein are impaired and the replication timing and subcellular localization of the Ebf1 locus are altered. Taken together, these data suggest that the regulation of Ebf1 via distinct promoters allows for the generation of several feedback loops and the coordination of multiple determinants of B lymphopoiesis in a regulatory network.
B淋巴细胞的早期分化需要多种转录因子的作用，这些转录因子调控着该谱系的特化和定向分化。功能缺失和功能获得实验为B淋巴细胞生成的转录调控提供了重要见解，据此推测E2A在EBF1上游起作用，而Pax5在EBF1下游起作用。然而，这种简单的层级关系无法解释所有观察结果，而且我们对转录因子和信号通路在其中发挥作用的假定调控网络的理解也很有限。在此，我们表明Ebf1基因的表达涉及两个受不同调控的启动子，它们产生不同的蛋白质异构体。我们发现白细胞介素-7信号、E2A和EBF1激活远端Ebf1启动子，而Pax5与Ets1和Pu.1共同调节更强的近端启动子。在缺乏Pax5的情况下，近端Ebf1启动子的功能和EBF1蛋白的积累受损，Ebf1基因座的复制时间和亚细胞定位也发生改变。综上所述，这些数据表明通过不同启动子对Ebf1的调控允许在调控网络中产生多个反馈环并协调B淋巴细胞生成的多个决定因素。
