Expression of antibody heavy chain occurs via precisely timed developmental activation of the immunoglobulin heavy chain (IgH) gene locus during B cell development. IgH locus activation permits coordinated gene rearrangements that assemble variable (VH), diversity (DH), and joining (JH) gene segments into functional genes. Chromosomal conformation changes and epigenetic mechanisms play critical roles in ensuring rearrangement fidelity while minimizing hazardous consequences of broken DNA ends generated during recombination. In this review, we summarize the current status of regulatory mechanisms that underpin effective IgH gene assembly. For this, the germline locus is divided into two parts: a 2.4Mb 5' part that contains all VH gene segments and a 300kb 3' domain that contains DH and JH gene segments, as well as exons that encode IgH isotypes. Structural features of each part are discussed individually, followed by consideration of how the two parts come together to complete IgH recombination. Throughout we emphasize current insights, propose plausible mechanisms, and highlight key questions for future studies.
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