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Vol. 12, No. 12, pp. 1801-1811, June 15, 1998
chain monoallelic demethylation and the establishment of
allelic exclusion
1 The Hubert H. Humphrey Center for Experimental Medicine
and Cancer Research, and
2 Department of Cellular
Biochemistry, The Hebrew University Hadassah Medical School, Jerusalem
91120, Israel;
3 Whitehead Institute for Biomedical
Research, Nine Cambridge Center, Cambridge, Massachusetts 02142 USA;
4 Max-Planck Institute for Immunobiology, Freiburg,
Germany 79108;
5 Department of Biology, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139 USA
Allelic exclusion in 
light-chain synthesis is thought to
result from a feedback mechanism by which the expression of a
functional 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 alleles for rearrangement. Analysis of + B-cell
populations and of individual + 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'
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 allele for
rearrangement.
[Key Words: Methylation; allelic exclusion; immunoglobulin; B lymphocytes]
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