Although much has been done to understand how rearrangement of the Igκ locus is regulated during B-cell development, little is known about the way the variable (V) segments themselves are selected. Here we show, using B6/Cast hybrid pre-B-cell clones, that a limited number of V segments on each allele is stochastically activated as characterized by the appearance of non-coding RNA and histone modifications. The activation states are clonally distinct, stable across cell division and developmentally important in directing the Ig repertoire upon differentiation. Using a new approach of allelic ATAC-seq, we demonstrate that the Igκ V alleles have differential chromatin accessibility, which may serve as the underlying basis of clonal maintenance at this locus, as well as other instances of monoallelic expression throughout the genome. These findings highlight a new level of immune system regulation that optimizes gene diversity.
Bibliographical noteFunding Information:
This research was supported by grants from the European Research Council (grant no. 268614 to H.C.), the Israel Cancer Research Fund (H.C. and Y.B.), the US-Israel Binational Foundation (Y.B., grant no. 2015506 to S.K.), the Rosetrees Foundation (H.C.), the Biological and Biotechnological Scientific Research Council (A.E.C. and L.M.), the I-CORE Program of ISF (Y.B. and H.C.), The Israel-China Binational ISF-NSFC (Y.B.) and the Emanuel Rubin Chair in Medical Science (Y.B.).
© The Author(s) 2017.