title: Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells.
abstract: In developing B cells, the immunoglobulin heavy chain (IgH) locus is thought to move from repressive to permissive chromatin compartments to facilitate its scheduled rearrangement. In mature B cells, maintenance of allelic exclusion has been proposed to involve recruitment of the non-productive IgH allele to pericentromeric heterochromatin. Here, we used an allele-specific chromosome conformation capture combined with sequencing (4C-seq) approach to unambigously follow the individual IgH alleles in mature B lymphocytes. Despite their physical and functional difference, productive and non-productive IgH alleles in B cells and unrearranged IgH alleles in T cells share many chromosomal contacts and largely reside in active chromatin. In brain, however, the locus resides in a different repressive environment. We conclude that IgH adopts a lymphoid-specific nuclear location that is, however, unrelated to maintenance of allelic exclusion. We additionally find that in mature B cells-but not in T cells-the distal VH regions of both IgH alleles position themselves away from active chromatin. This, we speculate, may help to restrict enhancer activity to the productively rearranged VH promoter element.
authors.affiliation: Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands.
authors.forename: Sjoerd J B
authors.initials: SJ
authors.lastname: Holwerda
authors.forename: Harmen J G
authors.initials: HJ
authors.lastname: van de Werken
authors.forename: Claudia
authors.initials: C
authors.lastname: Ribeiro de Almeida
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Bergen
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.forename: Marjon J A M
authors.initials: MJ
authors.lastname: Verstegen
authors.forename: Marieke
authors.initials: M
authors.lastname: Simonis
authors.forename: Erik
authors.initials: E
authors.lastname: Splinter
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Wijchers
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
mesh_terms: D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D002467:Cell Nucleus / Q000737:chemistry; D002843:Chromatin / Q000737:chemistry; D033481:Chromosomes, Mammalian; D050438:Genes, Immunoglobulin Heavy Chain; D056426:Genetic Loci; D007143:Immunoglobulin Heavy Chains / Q000032:analysis / Q000096:biosynthesis; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region