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Regulated large-scale nucleosome density patterns and precise nucleosome
positioning correlate with V(D)J recombination
#MMPMID27698124
Pulivarthy SR
; Lion M
; Kuzu G
; Matthews AG
; Borowsky ML
; Morris J
; Kingston RE
; Dennis JH
; Tolstorukov MY
; Oettinger MA
Proc Natl Acad Sci U S A
2016[Oct]; 113
(42
): E6427-E6436
PMID27698124
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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.
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