The Markings of Diversity

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Science  06 Jul 2007:
Vol. 317, Issue 5834, pp. 18
DOI: 10.1126/science.317.5834.18b

Antibody diversity in B cells is achieved through the somatic rearrangement of variable-(diversity)-joining [V(D)J] genetic segments. Allelic exclusion ensures that only one recombined allele is expressed in a given cell, in part through the selective acquisition of epigenetic marking by demethylation of the allele that is to undergo rearrangement.

Fraenkel et al. show that a second major mechanism, which further enhances antibody diversity and is known as somatic hypermutation (SHM), is under the same allele-restricted control. They generated mice in which developing B cells were engineered to carry a pre-rearranged antibody kappa light chain at both alleles. In these cells, both alleles, rather than only one, were expressed, yet demethylation and extensive hypermutation were confined to just one of the two. Thus, although differences in methylation did not influence the level of transcription after recombination (explaining how both rearranged alleles could be expressed in this system), these differences did correspond to SHM levels. The findings suggest that the same epigenetic marking system that mandates monoallelic expression of productively recombined alleles also targets the rearranged antibody genes for further mutation, and that this discrimination occurs independently of transcription in mature B cells. — SJS

Nat. Immunol. 8, 715 (2007).

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