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.
Highlights
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
Flow cytometric analysis further demonstrated significant decreases in the CD3e+ T cell and B220+ B cell counts in the peripheral blood of Mx1-Cre+;Setd2f/f mice (Fig. 1f, g). Consistent with these results, the counts of bone marrow nucleated cells (BMNCs) and bone marrow lymphocytes were significantly decreased in Mx1-Cre+; Setd2f/f mice (Fig. 1h–j) Taken together, these findings suggest that Setd[2] is actively involved in lymphoid lineage differentiation
We investigated whether the binding of Rag[1] to the TCRβ gene was altered by the removal of H3K36me[3] in thymocytes
Summary
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. While H3K36me[3] is normally enriched at the TCRβ locus, Setd[2] deficiency reduces TCRβ H3K36me[3] and suppresses TCRβ V(D)J rearrangement by impairing RAG1 binding to TCRβ loci and the DNA double-strand break repair. The repertoire of TCRs and immunoglobulins is generated through somatic DNA rearrangements of V, D, and J gene segments during early T and B cell lymphopoiesis. We further identify that loss of Setd[2] lead to the decreased accessibility of RAG1 to antigen receptor gene loci and insensitivity of DSB repair response in early lymphocytes
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