Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci
Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci
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DOI：
10.1084/jem.20090756
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发表时间：
2009-09-28
影响因子：
15.3
通讯作者：
Murre, Cornelis
中科院分区：
文献类型：
--
作者：
Beck, Kristina;Peak, Mandy M.;Murre, Cornelis
E2 A基因产物E12和E47是B细胞发育的关键调节因子。然而，E12和E47在B淋巴细胞生成过程中是否具有重叠和/或不同的功能仍然是未知的。我们已经产生了E12或E47缺陷的小鼠，并研究了它们在B细胞成熟中的作用。我们发现，E47是必不可少的前原B细胞阶段的发展进程，而E12是早期B细胞的发展，承诺和维护。相反，E12和E47在前B和未成熟B细胞中起关键作用，以促进免疫球蛋白λ（IG λ）种系转录以及IG λ VJ基因重排。此外，我们表明E12以及E47是在暴露于自身抗原时促进受体编辑所必需的。我们证明，E12和E47水平的增加可诱导IG lambda种系转录，促进组蛋白3（H3）上的三甲基化赖氨酸4以及J lambda区域的H3乙酰化，并激活IG lambda VJ基因重排。我们建议，在前B和未成熟的B细胞室，梯度E12和E47活动建立机械调节顺序重排的IG轻链基因。
The E2A gene products, E12 and E47, are critical regulators of B cell development. However, it remains elusive whether E12 and E47 have overlapping and/or distinct functions during B lymphopoiesis. We have generated mice deficient for either E12 or E47 and examined their roles in B cell maturation. We show that E47 is essential for developmental progression at the prepro-B cell stage, whereas E12 is dispensable for early B cell development, commitment, and maintenance. In contrast, both E12 and E47 play critical roles in pre-B and immature B cells to promote immunoglobulin lambda(Ig lambda) germline transcription as well as Ig lambda VJ gene rearrangement. Furthermore, we show that E12 as well as E47 is required to promote receptor editing upon exposure to self-antigen. We demonstrate that increasing levels of E12 and E47 act to induce Ig lambda germline transcription, promote trimethylated lysine 4 on histone 3 (H3) as well as H3 acetylation across the J lambda region, and activate Ig lambda VJ gene rearrangement. We propose that in the pre-B and immature B cell compartments, gradients of E12 and E47 activities are established to mechanistically regulate the sequential rearrangement of the Ig light chain genes.