title: Control of antigen receptor diversity through spatial regulation of V(D)J recombination.
abstract: Lymphocytes recognize a vast variety of pathogens by expressing a diverse repertoire of antigen receptor genes that are assembled by V(D)J recombination in immature B cells (Igh, Igk) and T cells (Tcrb, 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) Mb pairs. All antigen receptor loci undergo reversible contraction at the developmental stage, where they engage in V-(D)J recombination. This long-range looping promotes the participation of all V genes in V-(D)J recombination by juxtaposing distant V genes next to (D)J segments in the proximal recombination center. The B-cell-specific Pax5, ubiquitous YY1, and architectural CTCF/cohesin proteins promote 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 are likely involved in the regulation of VH-DJH recombination by mediating locus contraction. Notably, the large VH gene cluster of the Igh locus undergoes flexible long-range looping that ensures similar participation of all VH genes in VH-DJH recombination to generate a diverse antibody repertoire.
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Ebert
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria.
authors.forename: Jasna
authors.initials: J
authors.lastname: Medvedovic
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Tagoh
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Schwickert
authors.affiliation: Research Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria busslinger@imp.ac.at.
authors.forename: Meinrad
authors.initials: M
authors.lastname: Busslinger
mesh_terms: D000483:Alleles; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002843:Chromatin / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D006801:Humans; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008957:Models, Genetic; D005810:Multigene Family; D016296:Mutagenesis; D011485:Protein Binding; D011946:Receptors, Antigen / Q000235:genetics* / Q000276:immunology; D014157:Transcription Factors / Q000378:metabolism; D060152:V(D)J Recombination; D045567:VDJ Recombinases / Q000378:metabolism*
chemical_list: D000906:Antibodies; D002843:Chromatin; D011946:Receptors, Antigen; D014157:Transcription Factors; D045567:VDJ Recombinases