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V? gene repertoire and locus contraction are specified by critical DNase I hypersensitive sites within the V?-J? intervening region.

ABSTRACT: The processes of Ig gene locus contraction and looping during V(D)J-recombination are essential for creating a diverse Ab repertoire. However, no cis-acting sequence that plays a major role in specifying locus contraction has been uncovered within the Ig? gene locus. In this article, we demonstrate that a 650-bp sequence corresponding to DNase I hypersensitive sites HS1-2 within the mouse Ig? gene V-J intervening region binds CCCTC-binding factor and specifies locus contraction and long-range V? gene usage spanning 3.2 Mb in pre-B cells. We call this novel element Cer (for "contracting element for recombination"). Targeted deletion of Cer caused markedly increased proximal and greatly diminished upstream V? gene usage, higher allele usage, more splenic Ig?(+) B cells, and nonlineage-specific Ig? rearrangement in T cells. Relative to wild-type mice, Cer-deletion mice exhibited similar levels of V? gene germline transcription and H3K4me3 epigenetic marks but displayed a dramatic decrease in locus contraction in pre-B cells. Thus, our studies demonstrate that DNase I hypersensitive sites HS1-2 within the V?-J? intervening region are essential for controlling locus contraction and creating a diverse Ab repertoire.

SUBMITTER: Xiang Y

PROVIDER: S-EPMC3563863 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Vκ gene repertoire and locus contraction are specified by critical DNase I hypersensitive sites within the Vκ-Jκ intervening region.

Xiang Yougui Y Park Sung-Kyun SK Garrard William T WT

Journal of immunology (Baltimore, Md. : 1950) 20130107 4

The processes of Ig gene locus contraction and looping during V(D)J-recombination are essential for creating a diverse Ab repertoire. However, no cis-acting sequence that plays a major role in specifying locus contraction has been uncovered within the Igκ gene locus. In this article, we demonstrate that a 650-bp sequence corresponding to DNase I hypersensitive sites HS1-2 within the mouse Igκ gene V-J intervening region binds CCCTC-binding factor and specifies locus contraction and long-range Vκ ...[more]

PMID: 23296705

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Project description:Clarification of the mechanisms underlying osteoclast differentiation enable us to understand the physiology of bone metabolism as well as the pathophysiology of bone diseases, such as osteoporosis. Recently, it has been reported that epigenetics can determine the cell fate and regulate cell type specific gene expression. However, little is known about epigenetics during osteoclastogenesis. To reveal a part of epigenetics, especially focused on chromatin dynamics, during early osteoclastogenesis and identify novel transcription factors involved in osteoclastogenesis, we investigated genome-wide analysis of open chromatin during receptor activator of nuclear factor-M-NM-:B ligand (RANKL)-induced osteoclastogenesis using DNase I hypersensitive sites sequencing (DNase-seq). DNase-seq was performed using the extracted nuclei obtained from RAW264 cells treated with or without RANKL for 24 hours, followed by several bioinformatic analyses. DNase I hypersensitive sites (DHSs) during RANKL-induced osteoclastogenesis were dynamically changed and accumulated in promoter regions, although the distributions of DHSs among cis-regulatory DNA regions were identical regardless of RANKL stimulation. Motif discoveries from DHSs successfully identified well-known osteoclastogenic transcription factors such as Jun, CREB1, FOS, ATF2 and ATF4, but also novel transcription factors for osteoclastogenesis such as Zscan10, Atf1 Nrf1 and Srebf2. siRNA knockdown of these identified novel transcription factors impaired osteoclastogenesis. Taken together, DNase-seq can be a useful tool for comprehension of epigenetics, especially chromatin dynamics during osteoclastogenesis and for identification of novel transcription factors involved in osteoclastogenesis. This study may reveal underlying mechanisms that determine cell-type specific differentiation of bone cells and may lead to investigate novel therapeutic targets for osteoporosis. Examination of genome-wide DNase Hypersensitive Sites in differentiated and undifferentiated RAW264 cells.

Dataset Information

V? gene repertoire and locus contraction are specified by critical DNase I hypersensitive sites within the V?-J? intervening region.

Publications

Vκ gene repertoire and locus contraction are specified by critical DNase I hypersensitive sites within the Vκ-Jκ intervening region.

Similar Datasets

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