Accessibility control of V(D)J recombination

Mammals contend with a universe of evolving pathogens by generating an enormous diversity of antigen receptors during lymphocyte development. Precursor B and T cells assemble functional immunoglobulin (Ig) and T cell receptor (TCR) genes via recombination of numerous variable (V), diversity (D), and joining (J) gene segments. Although this combinatorial process generates significant diversity, genetic reorganization is inherently dangerous. Thus, V(D)J recombination must be tightly regulated to ensure proper lymphocyte development and avoid chromosomal translocations that cause lymphoid tumors. Each genomic rearrangement is mediated by a common V(D)J recombinase that recognizes sequences flanking all antigen receptor gene segments. The specificity of V(D)J recombination is due, in large part, to changes in the accessibility of chromatin at target gene segments, which either permits or restricts access to recombinase. The chromatin configuration of antigen receptor loci is governed by the concerted action of enhancers and promoters, which function as accessibility control elements (ACEs). In general, ACEs act as conduits for transcription factors, which in turn recruit enzymes that covalently modify or remodel nucleosomes. These ACE-mediated alterations are critical for activation of gene segment transcription and for opening chromatin associated with recombinase target sequences. In this chapter, we describe advances in understanding the mechanisms that control V(D)J recombination at the level of chromatin accessibility. The discussion will focus on cis-acting regulation by ACEs, the nuclear factors that control ACE function, and the epigenetic modifications that establish recombinase accessibility.