The DNA-Binding Protein CTCF Limits Proximal Vκ Recombination and Restricts κ Enhancer Interactions to the Immunoglobulin κ Light Chain Locus
The DNA-Binding Protein CTCF Limits Proximal Vκ Recombination and Restricts κ Enhancer Interactions to the Immunoglobulin κ Light Chain Locus
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DOI：
10.1016/j.immuni.2011.07.014
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发表时间：
2011-10-28
期刊：
影响因子：
32.4
通讯作者：
Hendriks, Rudi W.
中科院分区：
文献类型：
--
作者：
de Almeida, Claudia Ribeiro;Stadhouders, Ralph;Hendriks, Rudi W.
免疫球蛋白（IG）V（D）J基因重排的调节依赖于染色质的高级结构。在这里，我们研究了DNA结合锌指蛋白CTCF的体内功能，它调节增强子和启动子之间的相互作用。通过在B细胞系中条件性缺失CTCF基因，我们证明CTCF的缺失允许IG重链重组，但前B细胞增殖和分化严重受损。在不存在CTCF的情况下，IG κ轻链基因座显示近端V κ使用增加和远端V κ使用减少。这与增强的近端V κ和减少的J κ生殖系转录有关。染色体构象捕获实验表明，CTCF限制了IG κ增强子与近端V（κ）基因区域的相互作用，并防止这些强增强子与IG κ基因座外的元件之间的不适当相互作用。因此，尽管IG基因重组可以在CTCF不存在的情况下发生，但它是决定重组的V κ区段选择的关键因素。
Regulation of immunoglobulin (Ig) V(D)J gene rear-rangement is dependent on higher-order chromatin organization. Here, we studied the in vivo function of the DNA-binding zinc-finger protein CTCF, which regulates interactions between enhancers and promoters. By conditional deletion of the Ctcf gene in the B cell lineage, we demonstrate that loss of CTCF allowed Ig heavy chain recombination, but pre-B cell proliferation and differentiation was severely impaired. In the absence of CTCF, the Ig kappa light chain locus showed increased proximal and reduced distal V kappa usage. This was associated with enhanced proximal V kappa and reduced J kappa germline transcription. Chromosome conformation capture experiments demonstrated that CTCF limits interactions of the Ig kappa enhancers with the proximal V(kappa) gene region and prevents inappropriate interactions between these strong enhancers and elements outside the Ig kappa locus. Thus, although Ig gene recombination can occur in the absence of CTCF, it is a critical factor determining V kappa segment choice for recombination.