On July 26, 2019, Helen He Zhu from State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Clinical Stem Cell Research Center, and Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Wei-Qiang Gao and Li Li , School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, and Jinqiao Sun, Genetic Center, Children’s Hospital of Fudan University, collaborated to publish newly research “The histone methyltransferase Setd2 is indispensable for V(D)J recombination” on Nature Communications, which discovered the important role of the histone H3K36me3 methyltransferase SETD2 in the development of lymphocyte lineages. It is revealed that the epigenetic modification of H3K36Me3 is indispensable in the VDJ rearrangement process.

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. In this article, they showed 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.

The article’s first author is Zhongzhong Ji, a doctoral student at the School of Biomedical Engineering, Shanghai Jiao Tong University. This study is also supported by Dr. Jian Hou and Dr. Lijing Shen from Renji Hospital.

Article Link: https://doi.org/10.1038/s41467-019-11282-x

Reference:

1. von Boehmer, H. & Melchers, F. Checkpoints in lymphocyte development and autoimmune disease. Nat. Immunol. 11, 14–20 (2010).

2. Rothenberg, E. V. Transcriptional Control of Early T and B Cell Developmental Choices. Annu. Rev. Immunol. 32, 283–321 (2014).

3. Ji, Z. et al. The histone methyltransferase Setd2 is indispensable for V(D)J recombination. Nat. Commun. 10, 3353 (2019).