Flexible Long-Range Loops in the VH Gene Region of the Igh Locus Facilitate the Generation of a Diverse Antibody Repertoire

•Local interaction domains determine the Igh locus structure in lymphoid progenitors•Diverse antibody repertoire generated due to flexible loops in the VH gene cluster•Long-range interactions depend on the regulators Pax5, YY1, and CTCF•Regulatory elements in the proximal Igh region have no role in locus contraction

SummaryThe immunoglobulin heavy-chain (Igh) locus undergoes large-scale contraction in pro-B cells, which facilitates VH-DJH recombination by juxtaposing distal VH genes next to the DJH-rearranged gene segment in the 3′ proximal Igh domain. By using high-resolution mapping of long-range interactions, we demonstrate that local interaction domains established the three-dimensional structure of the extended Igh locus in lymphoid progenitors. In pro-B cells, these local domains engaged in long-range interactions across the Igh locus, which depend on the regulators Pax5, YY1, and CTCF. The large VH gene cluster underwent flexible long-range interactions with the more rigidly structured proximal domain, which probably ensures similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire. These long-range interactions appear to be an intrinsic feature of the VH gene cluster, because they are still generated upon mutation of the Eμ enhancer, IGCR1 insulator, or 3′ regulatory region in the proximal Igh domain.

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