Ensuring an equal playing field for antigen receptor loci variable regions

During the developmental progression of lymphoid progenitors, antigen receptor loci are assembled from variable (V), diversity (D), and joining (J) gene segments. In precursor B cells, the immunoglobulin heavy chain (Igh) locus undergoes ordered gene segment rearrangement with D H J H joining preceding V H to D H J H rearrangement. Similarly, in progenitor T lineage cells, the T cell receptor b chain is assembled from V, D, and J elements, whereas the TCRa chain is generated from the joining of V and J elements. The ordered rearrangement of the Igh locus is controlled by an insulator element, characterized by two CTCF binding sites, named the intergenic control region 1 (IGCR1), located between the V H and D H J H region. The IGCR1 helps to equalize antibody repertoires by suppressing transcription of proximal VH regions and their recombination with D H elements that have not yet joined with J H regions. Likewise, the Vk regions are segregated from the Jk regions by regulatory elements, named Cer and Sis, which antagonize transcription across the proximal Vk regions and suppress proximal VkJk recombination. In this issue, Majumder et al. provide new mechanistic insights into how regulatory elements help mediate appropriate long-range rearrangements between V elements and DJ regions involving the TCRb locus. The authors dissect a genomic region separating the TCR Vb from the DbJb elements. They identify two elements within the insulator: a distally located high affinity CTCF biding site and a more proximal region characterized by relatively weak CTCF binding. They found that the most distally located CTCF-containing element functions as an anchor to promote looping of distal Vb regions to the DbJb region, essentially promoting locus contraction. The second element, located most proximally to the DbJb region, acts as a barrier to prevent the spreading of active chromatin associated with the DbJb region into the CTCF anchor. However, removal of the proximal element interferes with the ability of the distal element to promote locus contraction. Thus, these findings point to a separation of function for binding sites associated with insulator elements: anchors that promote long-range contraction must be protected from transcriptionally active chromatin by boundary elements. The data presented by Majumder et al. indicate that the presence of a bifunctional insulator-anchoring element ensures an equal playing field for the Vb repertoire. Such bifunctional elements are not restricted to the TCRb locus. The IGCR1 element separating the V …