Asynchronous replication and allelic exclusion in the immune system

Raul Mostoslavsky, Nandita Singh, Toyoaki Tenzen, Maya Goldmit, Chana Gabay, Sharon Elizur, Peimin Qi, Benjamin E. Reubinoff, Andrew Chess, Howard Cedar () and Yehudit Bergman
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Raul Mostoslavsky: Hebrew University
Nandita Singh: Whitehead Institute for Biomedical Research
Toyoaki Tenzen: Hebrew University
Maya Goldmit: Hebrew University
Chana Gabay: Hebrew University
Sharon Elizur: Hebrew University
Peimin Qi: Whitehead Institute for Biomedical Research
Benjamin E. Reubinoff: Hadassah Ein-Kerem University Hospital
Andrew Chess: Whitehead Institute for Biomedical Research
Howard Cedar: Hebrew University
Yehudit Bergman: Hebrew University

Nature, 2001, vol. 414, issue 6860, 221-225

Abstract: Abstract 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 surface1,2. 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 molecule3, but recent work suggests that monoallelic epigenetic changes may also take place even before rearrangement4. 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 (μ, κ and λ) and the TCRβ 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.

Date: 2001
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DOI: 10.1038/35102606

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