title: Spatial Regulation of V-(D)J Recombination at Antigen Receptor Loci.
abstract: Lymphocytes express a diverse repertoire of antigen receptors, which are able to recognize a large variety of foreign pathogens. Functional antigen receptor genes are assembled by V(D)J recombination in immature B cells (Igh and Igk) and T cells (Tcr b and Tcra/d). V(D)J recombination takes place in the 3' proximal domain containing the D, J, and C gene segments, whereas 31 (Tcrb) to 200 (Igh) V genes are spread over a large region of 0.67 (Tcrb) to 3 (Igk) megabase pairs. The spatial regulation of V(D)J recombination has been best studied for the Igh locus, which undergoes reversible contraction by long-range looping in pro-B cells. This large-scale contraction brings distantly located VH genes into close proximity of the DJH-rearranged gene segment, which facilitates VH-DJH recombination. The B-cell-specific Pax5, ubiquitous YY1, and architectural CTCF/cohesin proteins regulate Igh locus contraction in pro-B cells by binding to multiple sites in the VH gene cluster. These regulators also control the pro-B-cell-specific activity of the distally located PAIR elements, which may be involved in the regulation of VH-DJH recombination by promoting locus contraction. Moreover, the large VH gene cluster of the Igh locus undergoes flexible long-range looping, which guarantees similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire. Importantly, long-range looping is a more general regulatory principle, as other antigen receptor loci also undergo reversible contraction at the developmental stage, where they engage in V-(D)J recombination.
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Ebert
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Louisa
authors.initials: L
authors.lastname: Hill
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria. Electronic address: busslinger@imp.ac.at.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D011946:Receptors, Antigen / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D060152:V(D)J Recombination
chemical_list: D011946:Receptors, Antigen
keywords: Antigen receptor loci; CTCF; Cohesin; Immunoglobulin heavy-chain gene; Locus contraction; Long-range looping; Pax5; Recombination center; V–DJ recombination; YY1