Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells |
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Authors: | Sjoerd J B Holwerda Harmen J G van de Werken Claudia Ribeiro de Almeida Ingrid M Bergen Marjolein J W de Bruijn Marjon J A M Verstegen Marieke Simonis Erik Splinter Patrick J Wijchers Rudi W Hendriks Wouter de Laat |
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Institution: | 1.Hubrecht Institute-KNAW & University Medical Center Utrecht, Utrecht 3584 CT, The Netherlands and 2.Department of Pulmonary Medicine, Erasmus MC Rotterdam, Rotterdam, Box 2040, 3000 CA, The Netherlands |
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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. |
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