Epigenetic programming of allelic extinction

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 surface. In fact, about 10% of the genome is transcribed in a monoallelic manner, with some cells expressing the maternal allele, and others the paternal allele in the target tissue. Little is known about how this phenomenon is regulated and programmed during development. Since many of the monoallelically-expressed genes were found to replicate asynchronously (AS), it is thought that the differential replication pattern in each cell may be involved in choosing one allele over the other. By taking advantage of stable clonal pre-B cell populations derived from C57BL6/Castaneous mice, we have mapped the genome-wide AS-replicating regions AS-RT loci, independently of genetic differences. These regions are characterized by differential chromatin accessibility, mono-allelic expression and include new gene families involved in specifying cell identity. By combining population level mapping with single cell FISH, our data reveal the existence of a novel regulatory program that coordinates a fixed relationship between AS-RT regions on any given chromosome, with some loci set to replicate in a parallel and others set in the anti-parallel orientation. Our results show that AS-RT is a highly regulated epigenetic mark established during early embryogenesis that may be used for facilitating the programming of mono-allelic choice throughout development.