Variable (V), diversity (D), and joining (J) (V(D)J) recombination is the first determinant of antigen receptor diversity. Understanding how recombination is regulated requires a comprehensive, unbiased readout of V gene usage. We have developed VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products. We reveal a 200-fold range of recombination efficiency among recombining V genes in the primary mouse Igh repertoire. We used machine learning to integrate these data with local chromatin profiles to identify combinatorial patterns of epigenetic features that associate with active V H gene recombination. These features localize downstream of V H genes and are excised by recombination, revealing a class of cis-regulatory element that governs recombination, distinct from expression. We detect two mutually exclusive chromatin signatures at these elements, characterized by CTCF/RAD21 and PAX5/IRF4, which segregate with the evolutionary history of associated V H genes. Thus, local chromatin signatures downstream of V H genes provide an essential layer of regulation that determines recombination efficiency.
VDJ-seq enables precise quantification of antibody V(D)J recombination products
Two distinct cis-regulatory designs characterize actively recombining V genes
Putative recombination regulatory elements map downstream of mouse Igh V genes
Recombination regulatory architecture reflects the V genes’ evolutionary history
Bolland et al. develop a technique to quantitatively profile antigen receptor diversity. Using VDJ-seq in the mouse Igh locus, they uncover the regulatory logic underlying the highly varying recombination rates of V gene segments, with implications for immune disorders and aberrant recombination in cancer.