Although most genes are expressed biallelically, a number of key genomic sites—including immune and olfactory receptor regions—are controlled monoallelically in a stochastic manner, with some cells expressing the maternal allele and others the paternal allele in the target tissue1,2. Very little is known about how this phenomenon is regulated and programmed during development. Here, using mouse immunoglobulin-κ (Igκ) as a model system, we demonstrate that although individual haematopoietic stem cells are characterized by allelic plasticity, early lymphoid lineage cells become committed to the choice of a single allele, and this decision is then stably maintained in a clonal manner that predetermines monoallelic rearrangement in B cells. This is accompanied at the molecular level by underlying allelic changes in asynchronous replication timing patterns at the κ locus. These experiments may serve to define a new concept of stem cell plasticity.
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We thank M. Nussenzweig for providing the Igκm/h mice, A. Waisman for providing the IiMOG-marked ES cells, A. G. Fisher and V. Azuara for guiding us through the replication timing analysis by S-phase fractionation assay, M. Inlay for coaching us on the purification and culturing of MPPs and CLPs, A. Wutz for providing some of the single-cell clones, Y. Smith for image analysis and L. Dempsey for sharing ideas. This work was supported by research grants from the Israel Academy of Sciences (H.C., Y.B.), National Institutes of Health (Y.B.), the Israel Cancer Research Foundation (H.C., Y.B.), the European Community 5th Framework Quality of Life Program (Y.B.), Lew Sanders (H.C.) and Norton Herrick (H.C.).
The authors declare no competing financial interests.
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Farago, M., Rosenbluh, C., Tevlin, M. et al. Clonal allelic predetermination of immunoglobulin-κ rearrangement. Nature 490, 561–565 (2012). https://doi.org/10.1038/nature11496
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