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The diverse repertoire of T cell receptors (TCR) and immunoglobulins is generated through the somatic rearrangement of respective V, D and J gene segments, termed V(D)J recombination, during early T or B cell development. However, epigenetic regulation of V(D)J recombination is still not fully understood. Here we show that the deficiency of Setd2, a histone methyltransferase that catalyzes lysine 36 trimethylation on histone 3 (H3K36me3) in mice, causes a severe developmental block of thymocytes at the CD4-CD8- DN3 stage. While H3K36me3 is normally enriched at the TCRβ locus, Setd2 deficiency reduces TCRβ H3K36me3 and suppresses TCRβ V(D)J rearrangement by impairing RAG1 binding to TCRβ loci and the DNA double-strand break repair. Similarly, Setd2 ablation also impairs immunoglobulin V(D)J rearrangement to induce B cell development block at the pro-B stage. Lastly, SETD2 is frequently mutated in patients with primary immunodeficiency. Our study thus demonstrates that Setd2 is required for optimal V(D)J recombination and normal lymphocyte development.


Zhongzhong Ji, Yaru Sheng, Juju Miao, Xiaoxia Li, Huifang Zhao, Jinming Wang, Chaping Cheng, Xue Wang, Kaiyuan Liu, Kai Zhang, Longmei Xu, Jufang Yao, Lijing Shen, Jian Hou, Wenhao Zhou, Jinqiao Sun, Li Li, Wei-Qiang Gao, Helen He Zhu. The histone methyltransferase Setd2 is indispensable for V(D)J recombination. Nature communications. 2019 Jul 26;10(1):3353

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PMID: 31350389

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