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Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):E6427-E6436. Epub 2016 Oct 3.

Regulated large-scale nucleosome density patterns and precise nucleosome positioning correlate with V(D)J recombination.

Author information

1
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; Department of Genetics, Harvard Medical School, Boston, MA 02115.
2
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114.
3
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; Department of Genetics, Harvard Medical School, Boston, MA 02115; Department of Biological Sciences, Wellesley College, Wellesley, MA 02481; Program in Biochemistry, Wellesley College, Wellesley, MA 02481.
4
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; Department of Genetics, Harvard Medical School, Boston, MA 02115; Department of Biological Science, Florida State University, Tallahassee, FL 32306.
5
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; tolstorukov@molbio.mgh.harvard.edu oettinger@molbio.mgh.harvard.edu.
6
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114; Department of Genetics, Harvard Medical School, Boston, MA 02115; tolstorukov@molbio.mgh.harvard.edu oettinger@molbio.mgh.harvard.edu.

Abstract

We show that the physical distribution of nucleosomes at antigen receptor loci is subject to regulated cell type-specific and lineage-specific positioning and correlates with the accessibility of these gene segments to recombination. At the Ig heavy chain locus (IgH), a nucleosome in pro-B cells is generally positioned over each IgH variable (VH) coding segment, directly adjacent to the recombination signal sequence (RSS), placing the RSS in a position accessible to the recombination activating gene (RAG) recombinase. These changes result in establishment of a specific chromatin organization at the RSS that facilitates accessibility of the genomic DNA for the RAG recombinase. In contrast, in mouse embryonic fibroblasts the coding segment is depleted of nucleosomes, which instead cover the RSS, thereby rendering it inaccessible. Pro-T cells exhibit a pattern intermediate between pro-B cells and mouse embryonic fibroblasts. We also find large-scale variations of nucleosome density over hundreds of kilobases, delineating chromosomal domains within IgH, in a cell type-dependent manner. These findings suggest that developmentally regulated changes in nucleosome location and occupancy, in addition to the known chromatin modifications, play a fundamental role in regulating V(D)J recombination. Nucleosome positioning-which has previously been observed to vary locally at individual enhancers and promoters-may be a more general mechanism by which cells can regulate the accessibility of the genome during development, at scales ranging from several hundred base pairs to many kilobases.

KEYWORDS:

V(D)J recombination; chromatin; epigenetics; lymphocytes; nucleosome positioning

PMID:
27698124
PMCID:
PMC5081657
DOI:
10.1073/pnas.1605543113
[Indexed for MEDLINE]
Free PMC Article

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