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, Shanghai, 200127, China.
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
Nat Commun. 2019 Jul 26;10(1):3353. doi: 10.1038/s41467-019-11282-x.
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 CD4CD8 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.
T 细胞受体 (TCR) 和免疫球蛋白的多样性库是通过早期 T 或 B 细胞发育过程中各自的 V、D 和 J 基因片段的体细胞重排产生的，称为 V(D)J 重组。然而，V(D)J 重组的表观遗传调控仍不完全清楚。在这里，我们表明，组蛋白甲基转移酶 Setd2 的缺乏会导致小鼠中组蛋白 3（H3）赖氨酸 36 三甲基化（H3K36me3）的催化，导致胸腺细胞在 CD4CD8 DN3 阶段的严重发育阻滞。虽然 H3K36me3 通常在 TCRβ 基因座上富集，但 Setd2 缺乏会通过损害 RAG1 与 TCRβ 基因座的结合以及 DNA 双链断裂修复来降低 TCRβ H3K36me3 并抑制 TCRβ V(D)J 重排。同样，Setd2 缺失也会损害免疫球蛋白 V(D)J 重排，导致前 B 细胞阶段的 B 细胞发育阻滞。最后，SETD2 在原发性免疫缺陷患者中经常发生突变。因此，我们的研究表明 Setd2 是最佳 V(D)J 重组和正常淋巴细胞发育所必需的。
