Intra- and interchromosomal contact mapping reveals the Igh locus has extensive conformational heterogeneity and interacts with B-lineage genes.

To produce a diverse antibody repertoire, immunoglobulin heavy-chain (Igh) loci undergo large-scale alterations in structure to facilitate juxtaposition and recombination of spatially separated variable (V H), diversity (D H), and joining (J H) genes. These chromosomal alterations are poorly understood. Uncovering their patterns shows how chromosome dynamics underpins antibody diversity. Using tiled Capture Hi-C, we produce a comprehensive map of chromatin interactions throughout the 2.8-Mb Igh locus in progenitor B cells. We find that the Igh locus folds into semi-rigid subdomains and undergoes flexible looping of the V H genes to its 3′ end, reconciling two views of locus organization. Deconvolution of single Igh locus conformations using polymer simulations identifies thousands of different structures. This heterogeneity may underpin the diversity of V(D)J recombination events. All three immunoglobulin loci also participate in a highly specific, developmentally regulated network of interchromosomal interactions with genes encoding B cell-lineage factors. This suggests a model of interchromosomal coordination of B cell development. [Display omitted] • Capture Hi-C maps intra- and interchromosomal contacts of the immunoglobulin heavy chain • Polymer modeling shows thousands of different Igh structures that underpin diversity • The Ig loci participate in a stage-specific interchromosomal network with B lineage genes Mielczarek et al. use Capture Hi-C to obtain a detailed map of chromosomal interactions within the immunoglobulin heavy-chain locus. Polymer modeling shows that each Igh structure is unique, enabling antibody diversity. The Ig loci associate with key B lineage genes in a developmental-stage-specific interchromosomal network. [ABSTRACT FROM AUTHOR]