Immunoglobulin heavy-chain (IgH) genes are assembled by DNA rearrangements that juxtapose a variable (V), a diversity (D), and a joining (J) gene segment. Here, we report that in the absence of intergenic control region 1 (IGCR1), the intronic enhancer (Eμ) associates with the next available CTCF binding site located close to V81X via putative heterotypic interactions involving YY1 and CTCF. The alternate Eμ/V81X loop leads to formation of a distorted recombination center and altered D rearrangements and disrupts chromosome conformation that favors distal V recombination. Cumulatively, these features drive highly skewed, Eμ-dependent recombination of V81X. Sequential deletion of CTCF binding regions on IGCR1-deleted alleles suggests that they influence recombination of single proximal V gene segments. Our observations demonstrate that Eμ interacts differently with IGCR1- or V-associated CTCF binding sites and thereby identify distinct roles for insulator-like elements in directing enhancer activity.

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