κ chain monoallelic demethylation and the establishment of allelic exclusion

Raul Mostoslavsky, Nandita Singh, Andrei Kirillov, Roberta Pelanda, Howard Cedar*, Andrew Chess, Yehudit Bergman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

Abstract

Allelic exclusion in κ light-chain synthesis is thought to result from a feedback mechanism by which the expression of a functional κ light chain on the surface of the B cell leads to an intracellular signal that down- regulates the V(D)J recombinase, thus precluding rearrangement of the other allele. Whereas such a feedback mechanism clearly plays a role in the maintenance of allelic exclusion, here we provide evidence suggesting that the initial establishment of allelic exclusion involves differential availability of the two κ alleles for rearrangement. Analysis of κ+ B- cell populations and of individual κ+ B cells that have rearranged only one allele demonstrates that in these cells, critical sites on the rearranged allele are unmethylated, whereas the nonrearranged allele remains methylated. This pattern is apparently generated by demethylation that is initiated at the small pre-B cell stage, on a single allele, in a process that occurs prior to rearrangement and requires the presence in cis of both the intronic and 3' κ enhancers. Taken together with data demonstrating that undermethylation is required for rearrangement, these results indicate that demethylation may actually underly the process of allelic exclusion by directing the initial choice of a single κ allele for rearrangement.

Original languageAmerican English
Pages (from-to)1801-1811
Number of pages11
JournalGenes and Development
Volume12
Issue number12
DOIs
StatePublished - 15 Jun 1998

Keywords

  • Allelic exclusion
  • B lymphocytes
  • Immunoglobulin
  • Methylation

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