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

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 TCR? locus, Setd2 deficiency reduces TCR? H3K36me3 and suppresses TCR? V(D)J rearrangement by impairing RAG1 binding to TCR? 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.

SUBMITTER: Ji Z 

PROVIDER: S-EPMC6659703 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature