Chromosomal Loop Domains Direct the Recombination of Antigen Receptor Genes

摘要: RAG initiates antibody V(D)J recombination in developing lymphocytes by generating "on-target" DNA breaks at matched pairs of bona fide signal sequences (RSSs). We employ bait RAG-generated endogenous or ectopically inserted RSS to identify huge numbers "off-target" breaks. Such occur the simple CAC motif that defines cleavage site and are largely confined within convergent CTCF-binding element (CBE)-flanked loop domains containing pairs. Marked orientation dependence off-target activity loops spanning up 2 megabases implies involvement linear tracking. In this regard, major off-targets chromosomal translocations as enhancers a loop. Finally, deletion CBE-based IgH locus disrupts and, correspondingly, alters on- distributions IgH. Our findings reveal how is developmentally focused implicate mechanisms which chromatin harness biological processes them.