A plant homeodomain in Rag-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement
A plant homeodomain in Rag-2 that binds hypermethylated lysine 4 of histone H3 is necessary for efficient antigen-receptor-gene rearrangement
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DOI：
10.1016/j.immuni.2007.09.005
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发表时间：
2007-10-01
期刊：
影响因子：
32.4
通讯作者：
Desiderio, Stephen
中科院分区：
文献类型：
--
作者：
Liu, Yun;Subrahmanyam, Ramesh;Desiderio, Stephen
V(D)J重组是由重组激活基因（RAG）蛋白RAG-1和RAG-2启动的。抗原受体基因片段进行V(D)J重组的能力与空间和时间限制的染色质修饰有关。我们发现RAG-2特异性地与组蛋白H3结合，并且这种结合完全依赖于赖氨酸4的二甲基化或三甲基化（H3K4me2或H3K4me3）。这种相互作用需要一个非规范植物同源结构域（non - canonical plant homeodomain， PHD），而这一结构域以前在rag2的非核心区域被描述过。rag2 PHD手指通过IgH D-J(H)-C位点与染色质结合，与三甲基化组蛋白h3k4的分布密切相关。rag2 PHD指中一个保守色氨酸残基的突变破坏了与H3K4me3的结合，并极大地损害了染色体外和内源性免疫球蛋白基因片段的重组。总之，这些发现与对高甲基化组蛋白H3 K4的识别促进体内有效的V(D)J重组的解释一致。
V(D)J recombination is initiated by the recombination activating gene (RAG) proteins RAG-1 and RAG-2. The ability of antigen-receptorgene segments to undergo V(D)J recombination is correlated with spatially- and temporallyrestricted chromatin modifications. We have found that RAG-2 bound specifically to histone H3 and that this binding was absolutely dependent on dimethylation or trimethylation at lysine 4 (H3K4me2 or H3K4me3). The interaction required a noncanonical plant homeodomain (PHD) that had previously been described within the noncore region of RAG-2. Binding of the RAG-2 PHD finger to chromatin across the IgH D-J(H)-C locus showed a strong correlation with the distribution of trimethylated histone H3 K4. Mutation of a conserved tryptophan residue in the RAG-2 PHD finger abolished binding to H3K4me3 and greatly impaired recombination of extrachromosomal and endogenous immunoglobulin gene segments. Together, these findings are consistent with the interpretation that recognition of hypermethylated histone H3 K4 promotes efficient V(D)J recombination in vivo.