Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells

TY - JOUR

T1 - Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells

AU - Holwerda, S.J.

AU - van de Werken, H.J.

AU - Ribeiro de Almeida, C.

AU - Bergen, I.M.

AU - de Bruijn, M.J.

AU - Verstegen, M.J.

AU - Simonis, M.

AU - Splinter, E.

AU - Wijchers, P.J.

AU - Hendriks, R.W.

AU - de Laat, W.

N1 - Reporting year: 2013

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

U2 - 10.1093/nar/gkt491

DO - 10.1093/nar/gkt491

M3 - Article

SN - 0305-1048

VL - 41

SP - 6905

EP - 6916

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 14

ER -