Stepwise Activation of Enhancer and Promoter Regions of the B Cell Commitment Gene Pax5 in Early Lymphopoiesis
Stepwise Activation of Enhancer and Promoter Regions of the B Cell Commitment Gene Pax5 in Early Lymphopoiesis
复制标题
DOI：
10.1016/j.immuni.2009.01.012
复制
发表时间：
2009-04-17
期刊：
影响因子：
32.4
通讯作者：
Busslinger, Meinrad
中科院分区：
文献类型：
--
作者：
Decker, Thorsten;di Magliano, Marina Pasca;Busslinger, Meinrad
Pax5是B细胞身份和功能的重要调节因子。在这里，我们使用转基因和缺失定位来鉴定Pax5基因座的内含子5中的一个有效增强子。该增强子与启动子区域的结合足以重现Pax5的B淋巴表达。该增强子在胚胎干细胞中被DNA甲基化沉默，但在多能造血祖细胞中被激活。它含有转录因子PU.1、IRF4、IRF8和NF-kappa B的功能结合位点，表明这些调节因子在造血祖细胞和B细胞发育过程中促进了序列增强子的激活。相比之下，启动子区域在非b细胞中被Polycomb组蛋白抑制，并且仅在前b细胞发育开始时通过转录因子EBF1诱导染色质重塑而被激活。这些实验证明Pax5在早期淋巴生成中是逐步激活的；并提供对B细胞承诺过程的机制见解。
Pax5 is an essential regulator of B cell identity and function. Here, we used transgenesis and deletion mapping to identify a potent enhancer in intron 5 of the Pax5 locus. This enhancer in combination with the promoter region was sufficient to recapitulate the B lymphoid expression of Pax5. The enhancer was silenced by DNA methylation in embryonic stem cells, but became activated in multipotent hematopoietic progenitors. It contained functional binding sites for the transcription factors PU.1, IRF4, IRF8, and NF-kappa B, suggesting that these regulators contribute to sequential enhancer activation in hematopoietic progenitors and during B cell development. In contrast, the promoter region was repressed by Polycomb group proteins in non-B cells and was activated only at the onset of pro-B cell development through induction of chromatin remodeling by the transcription factor EBF1. These experiments demonstrate a stepwise activation of Pax5 in early lymphopoiesis; and provide mechanistic insights into the process of B cell commitment.