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 alter-ations in structure to facilitate juxtaposition and recombination of spatially separated variable (VH), diversity (DH), and joining (JH) 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 VH genes to its 30 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.

Automated summary

This study utilized tiled Capture Hi-C to map chromatin interactions within the Igh locus in progenitor B cells, revealing semi-rigid subdomains and flexible looping of VH genes. Deconvolution of single Igh locus conformations identified thousands of different structures, potentially contributing to the diversity of V(D)J recombination events. Additionally, all three immunoglobulin loci were found to participate in a specific network of interchromosomal interactions with genes encoding B cell-lineage factors, suggesting a model of interchromosomal coordination in B cell development.