title: Nuclear positioning rather than contraction controls ordered rearrangements of immunoglobulin loci.
abstract: Progenitor-B cells recombine their immunoglobulin (Ig) loci to create unique antigen receptors. Despite a common recombination machinery, the Ig heavy and Ig light chain loci rearrange in a stepwise manner. We studied pre-pro-B cells and Rag(-/-) progenitor-B cells to determine whether Ig locus contraction or nuclear positioning is decisive for stepwise rearrangements. We found that both Ig loci were contracted in pro-B and pre-B cells. Igh relocated from the nuclear lamina to central domains only at the pro-B cell stage, whereas, Igκ remained sequestered at the lamina, and only at the pre-B cell stage located to central nuclear domains. Finally, in vitro induced re-positioning of Ig alleles away from the nuclear periphery increased germline transcription of Ig loci in pre-pro-B cells. Thus, Ig locus contraction juxtaposes genomically distant elements to mediate efficient recombination, however, sequential positioning of Ig loci away from the nuclear periphery determines stage-specific accessibility of Ig loci.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Magdalena B
authors.initials: MB
authors.lastname: Rother
authors.affiliation: Department of Biochemistry, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Robert-Jan
authors.initials: RJ
authors.lastname: Palstra
authors.affiliation: Department of Molecular Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA.
authors.forename: Suchit
authors.initials: S
authors.lastname: Jhunjhunwala
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Kevin A M
authors.initials: KA
authors.lastname: van Kester
authors.affiliation: Center for Biomics, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Pulmonary Medicine, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.affiliation: Department of Molecular Biology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA.
authors.forename: Cornelis
authors.initials: C
authors.lastname: Murre
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands menno.vanzelm@monash.edu.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D004843:Epistasis, Genetic; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains