Mostoslavsky R, Singh N, Tenzen T, Goldmit M, Gabay C, Elizur S, Qi P, Reubinoff B E, Chess A, Cedar H, Bergman Y
Department of Cellular Biochemistry & Human Genetics, and Experimental Medicine & Cancer Research, PO Box 12272, Hebrew University, Jerusalem 91120, Israel.
Nature. 2001 Nov 8;414(6860):221-5. doi: 10.1038/35102606.
The development of mature B cells involves a series of molecular decisions which culminate in the expression of a single light-chain and heavy-chain antigen receptor on the cell surface. There are two alleles for each receptor locus, so the ultimate choice of one receptor type must involve a process of allelic exclusion. One way to do this is with a feedback mechanism that downregulates rearrangement after the generation of a productive receptor molecule, but recent work suggests that monoallelic epigenetic changes may also take place even before rearrangement. To better understand the basis for distinguishing between alleles, we have analysed DNA replication timing. Here we show that all of the B-cell-receptor loci (mu, kappa and lambda) and the TCRbeta locus replicate asynchronously. This pattern, which is established randomly in each cell early in development and maintained by cloning, represents an epigenetic mark for allelic exclusion, because it is almost always the early-replicating allele which is initially selected to undergo rearrangement in B cells. These results indicate that allelic exclusion in the immune system may be very similar to the process of X chromosome inactivation.
成熟B细胞的发育涉及一系列分子决策，最终导致细胞表面表达单一的轻链和重链抗原受体。每个受体基因座有两个等位基因，因此选择一种受体类型的最终过程必然涉及等位基因排斥。一种实现方式是通过一种反馈机制，在产生有功能的受体分子后下调重排，但最近的研究表明，单等位基因的表观遗传变化甚至可能在重排之前就已发生。为了更好地理解区分等位基因的基础，我们分析了DNA复制时间。我们在此表明，所有B细胞受体基因座（μ、κ和λ）以及TCRβ基因座都是异步复制的。这种模式在发育早期的每个细胞中随机建立并通过克隆维持，代表了等位基因排斥的一种表观遗传标记，因为在B细胞中最初被选择进行重排的几乎总是早期复制的等位基因。这些结果表明，免疫系统中的等位基因排斥可能与X染色体失活过程非常相似。
