Xu Cheng-Ran, Feeney Ann J
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 2009 Feb 1;182(3):1362-9. doi: 10.4049/jimmunol.182.3.1362.
Ag receptor loci poised for V(D)J rearrangement undergo germline transcription (GT) of unrearranged genes, and the accessible gene segments are associated with posttranslational modifications (PTM) on histones. In this study, we performed a comprehensive analysis of the dynamic changes of four PTM throughout B and T cell differentiation in freshly isolated ex vivo cells. Methylation of lysines 4 and 79 of histone H3, and acetylation of H3, demonstrated stage and lineage specificity, and were most pronounced at the J segments of loci poised for, or undergoing, rearrangement, except for dimethylation of H3K4, which was more equally distributed on V, D, and J genes. Focusing on the IgL loci, we demonstrated there are no active PTM in the absence of pre-BCR signaling. The kappa locus GT and PTM on Jkappa genes are rapidly induced following pre-BCR signaling in large pre-B cells. In contrast, the lambda locus shows greatly delayed onset of GT and PTM, which do not reach high levels until the immature B cell compartment, the stage at which receptor editing is initiated. Analysis of MiEkappa(-/-) mice shows that this enhancer plays a key role in inducing not only GT, but PTM. Using an inducible pre-B cell line, we demonstrate that active PTM on Jkappa genes occur after GT is initiated, indicating that histone PTM do not make the Jkappa region accessible, but conversely, GT may play a role in adding PTM. Our data indicate that the epigenetic profile of IgL genes is dramatically modulated by pre-BCR signaling and B cell differentiation status.
准备进行V(D)J重排的抗原受体基因座会经历未重排基因的种系转录(GT)，并且可及的基因片段与组蛋白的翻译后修饰(PTM)相关。在本研究中，我们对新鲜分离的体外细胞在B细胞和T细胞分化过程中四种PTM的动态变化进行了全面分析。组蛋白H3赖氨酸4和79的甲基化以及H3的乙酰化表现出阶段和谱系特异性，并且在准备进行或正在进行重排的基因座的J片段处最为明显，但H3K4的二甲基化除外，其在V、D和J基因上分布更为均匀。聚焦于IgL基因座，我们证明在缺乏前B细胞受体(pre-BCR)信号时不存在活跃的PTM。在大前B细胞中，pre-BCR信号传导后，κ基因座的GT和Jκ基因上的PTM会迅速被诱导。相比之下，λ基因座的GT和PTM起始则大大延迟，直到未成熟B细胞阶段（即受体编辑开始的阶段）才达到高水平。对MiEkappa(-/-)小鼠的分析表明，该增强子不仅在诱导GT方面起关键作用，而且在诱导PTM方面也起关键作用。使用可诱导的前B细胞系，我们证明Jκ基因上的活跃PTM在GT开始后出现，这表明组蛋白PTM不会使Jκ区域变得可及，相反，GT可能在添加PTM中起作用。我们的数据表明，IgL基因的表观遗传特征受到pre-BCR信号和B细胞分化状态的显著调节。
