TY - CHAP
T1 - Accessibility Control of V(D)J Recombination
AU - Cobb, Robin Milley
AU - Oestreich, Kenneth J.
AU - Osipovich, Oleg A.
AU - Oltz, Eugene M.
N1 - Funding Information:
We are grateful to numerous colleagues for their valuable discussions over the years and apologize to any colleagues whose work may not have been cited. This work was supported by the following grants from the National Institutes of Health: P01 HL68744 and CA100905 to E.M.O., T32 HL69765 to R.M.C., T32 CA09385 to K.J.O., and a Cancer Center Support Grant (P30 CA68485) to the Vanderbilt‐Ingram Cancer Center.
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33747849302&partnerID=8YFLogxK
U2 - 10.1016/S0065-2776(06)91002-5
DO - 10.1016/S0065-2776(06)91002-5
M3 - Chapter
C2 - 16938538
AN - SCOPUS:33747849302
SN - 0120224917
SN - 9780120224913
T3 - Advances in Immunology
SP - 45
EP - 109
BT - Advances in Immunology
A2 - Alt, Frederik
ER -