Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development
Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development
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DOI：
10.1016/j.isci.2020.100941
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发表时间：
2020-03-27
期刊：
影响因子：
5.8
通讯作者：
Armstrong, Scott A.
中科院分区：
文献类型：
--
作者：
Chu, S. Haihua;Chabon, Jonathan R.;Armstrong, Scott A.
淋巴细胞发育过程中DNA双链断裂（DSBs）的修复是V(D)J重组的必要条件，也是免疫球蛋白可变区多样性的基础。历史上对这一过程的理解主要集中在RAG1/2重组酶和一组经典的非同源末端连接因子的研究上。关于染色质修饰在这一过程中的作用的报道少得多。在这里，我们展示了非冗余组蛋白H3赖氨酸甲基转移酶Setd2及其赖氨酸-36三甲基化修饰（H3K36me3）在V(D)J重组过程中DNA末端的加工和连接中的作用。缺失导致rag诱导的DNA dsb的错误修复，特别是当Atm激酶活性缺失时。此外，缺失会减少免疫库，严重阻断淋巴细胞生成，并导致有丝分裂后神经元凋亡。总之，这些研究提示Setd2/H3K36me3在受双链断裂修复影响的这两种哺乳动物发育过程中发挥重要作用。
Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, especially when combined with loss of Atm kinase activity. Furthermore, loss reduces immune repertoire and a severe block in lymphogenesis as well as causes post-mitotic neuronal apoptosis. Together, these studies are suggestive of an important role of Setd2/H3K36me3 in these two mammalian developmental processes that are influenced by double-stranded break repair.