Monoallelic gene expression, or allelic exclusion, is critical to the functioning of the immune system as it
allows each lymphocyte to elaborate an antigen receptor of a single type. Chaos in immune system
regulation might ensue if, for example, a B cell expressed both an antibody that responded to a pathogen
and a second antibody that would cause damage to a certain host system. It has been proposed that the
major pathway for implementing this choice is by a feedback mechanism in which the generation of a gene
product from one allele leads to inhibition of the recombination machinery, thereby preventing rearrangement
on the remaining germ line allele. While this mechanism may certainly play a maintenance role in inhibiting
rearrangement on the non-selected allele, recent evidence suggests that the process of allelic exclusion may
actually begin early in development, at about the time of implantation, when the antigen receptor genes
become asynchronously replicating in each cell. However, it is not yet known how this chromosomal mark
enables the initial selection of only one allele.
We have designed experiments using targeted transgenic mice to show that replication timing plays a critical
and direct role in controlling allelic exclusion. We will identify the molecular components that set up the
asynchronous pattern of replication. We have developed a unique clonal pre-B cell system that allows us to
decipher the monoallelic epigenetic processes such as chromatin modifications, unequal nuclear localization,
DMA methylation, and replication that leads to allelic exclusion. These epigenetic mechanisms may be very
similar to those that regulate the X-chromosome inactivation in female cells and parental genomic imprinting.
These studies will help us to understand how the diversity and specificity of the immune system are
generated and how this system functions to eliminate pathogens.