Histone reader BRWD1 targets and restricts recombination to the Igk locus.
Histone reader BRWD1 targets and restricts recombination to the Igk locus.
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DOI：
10.1038/ni.3249
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发表时间：
2015-10
影响因子：
30.5
通讯作者：
Clark MR
中科院分区：
文献类型：
--
作者：
Mandal M;Hamel KM;Maienschein-Cline M;Tanaka A;Teng G;Tuteja JH;Bunker JJ;Bahroos N;Eppig JJ;Schatz DG;Clark MR
B 淋巴细胞生成需要 RAG1-RAG2 重组酶能够接触到免疫球蛋白基因。然而，RAG 蛋白与开放染色质广泛结合，表明必须有其他机制限制 RAG 介导的 DNA 切割。在这里，我们证明了小前 B 细胞中白细胞介素 7 (IL-7) 受体信号传导的发育下调诱导了溴结构域家族成员 BRWD1 的表达，该成员被招募到由前 BCR 依赖性 Erk 激活决定的 Igk 的特定表观遗传景观中。 BRWD1 增强了 RAG 募集，增加了基因可及性，并将核小体定位在每个 Jκ 重组信号序列的 5' 端。因此，BRWD1 的重组目标是 Igk，并将重组置于控制 B 细胞发育的信号级联的背景下。我们的研究结果提供了一个范例，其中在任何特定的抗原受体位点，专门的机制强制谱系和阶段特异性重组。
B lymphopoiesis requires that immunoglobulin genes be accessible to the RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin suggesting that additional mechanisms must restrict RAG-mediated DNA cleavage. Here, we demonstrate developmental downregulation of interleukin 7 (IL-7) receptor signaling in small pre-B cells induced expression of the bromodomain family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre-BCR-dependent Erk activation. BRWD1 enhanced RAG recruitment, increased gene accessibility and positioned nucleosomes 5′ to each Jκ recombination signal sequence. BRWD1 thus targets recombination to Igk and places recombination within the context of signaling cascades that control B cell development. Our findings provide a paradigm in which, at any particular antigen receptor locus, specialized mechanisms enforce lineage and stage specific recombination.