Chromatin folding principles underlying the generation of antibody diversity

Effective adaptive immunity requires generation of a diverse repertoire of antigen receptors via V(D)J recombination. To illuminate the underlying mechanisms, we combined biophysical simulations with experimental data to model chromatin folding and dynamics of the mouse immunoglobulin heavy chain gene ( Igh ) locus. Simulations that best recapitulated experimental data on locus structure and recombination of Igh alleles identified three novel chromatin folding principles. First, we found that prominent structural features of the Igh locus, such as the 3′-anchored stripe, required cohesin loading throughout the locus. Second, the Eμ enhancer was best modeled as a bi-directional loop extrusion blocker, though it does not bind CTCF. Third, we found that utilization of V H genes to obtain maximum diversity required both widespread cohesin loading as well as long-range associations between H3K27ac-marked regions. Our findings provide a conceptual framework to understand chromatin folding principles that enable antibody diversity and reveal mechanisms of long-range genome communication. • Stripe anchor is a termination site for cohesin-mediated chromatin extrusion • Eμ enhancer is a CTCF-independent blocker of cohesin extrusion • Cohesin loading across the Igh locus recapitulates structure and recombination • H3K27ac associations in cohesin-generated structures promote distal interactions Ollikainen et al. combined biophysical simulations and experimental data to model chromatin structure and dynamics of the 3 Mb mouse Igh locus. The study reveals mechanisms of long-range genome communication and chromatin folding principles that enable antigen receptor diversity.