Two Forms of Loops Generate the Chromatin Conformation of the Immunoglobulin Heavy-Chain Gene Locus

The immunoglobulin heavy-chain (IgH) gene locus undergoes radial repositioning within the nucleus and locus contraction in preparation for gene recombination. We demonstrate that IgH locus conformation involves two levels of chromosomal compaction. At the first level, the locus folds into several multilooped domains. One such domain at the 3′ end of the locus requires an enhancer, Eμ; two other domains at the 5′ end are Eμ independent. At the second level, these domains are brought into spatial proximity by Eμ-dependent interactions with specific sites within the VH region. Eμ is also required for radial repositioning of IgH alleles, indicating its essential role in large-scale chromosomal movements in developing lymphocytes. Our observations provide a comprehensive view of the conformation of IgH alleles in pro-B cells and the mechanisms by which it is established. [Display omitted] ► The Eμ enhancer is required for radial repositioning of IgH alleles in pro-B cells ► CTCF-containing chromatin loops fold the VH region into Eμ-independent domains ► Eμ nucleates a three-loop domain at the 3′ end of the IgH locus ► Eμ interacts with the VH region to juxtapose 5′ and 3′ ends of the IgH locus An enhancer reconfigures the immunoglobulin heavy-chain locus to compact the chromatin, creating multiloop domains and bringing them together for recombination.