The histone methyltransferase Setd2 is indispensable for V(D)J recombination

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 () and Helen He Zhu ()
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Zhongzhong Ji: Shanghai Jiao Tong University
Yaru Sheng: Shanghai Jiao Tong University
Juju Miao: Shanghai Jiao Tong University
Xiaoxia Li: Shanghai Jiao Tong University
Huifang Zhao: Shanghai Jiao Tong University
Jinming Wang: Shanghai Jiao Tong University
Chaping Cheng: Shanghai Jiao Tong University
Xue Wang: Shanghai Jiao Tong University
Kaiyuan Liu: Shanghai Jiao Tong University
Kai Zhang: Shanghai Jiao Tong University
Longmei Xu: Shanghai Jiao Tong University
Jufang Yao: Shanghai Jiao Tong University
Lijing Shen: Shanghai Jiao Tong University
Jian Hou: Shanghai Jiao Tong University
Wenhao Zhou: Children’s Hospital of Fudan University
Jinqiao Sun: Children’s Hospital of Fudan University
Li Li: Shanghai Jiao Tong University
Wei-Qiang Gao: Shanghai Jiao Tong University
Helen He Zhu: Shanghai Jiao Tong University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11282-x

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