Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development

Summary Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, especially when combined with loss of Atm kinase activity. Furthermore, loss reduces immune repertoire and a severe block in lymphogenesis as well as causes post-mitotic neuronal apoptosis. Together, these studies are suggestive of an important role of Setd2/H3K36me3 in these two mammalian developmental processes that are influenced by double-stranded break repair.
Graphical Abstract
Highlights • Setd2/H3K36me3 is essential in maintaining a normal hematopoiesis • Loss of Setd2/H3K36me3 impairs lymphogenesis and V(D)J recombination • Loss of Setd2/H3K36me3 and ATM kinase activity leads to mis-repaired recombination • Setd2/H3K36me3 prevents apoptosis of post-mitotic neuronal cells
Biological Sciences; Molecular Biology; Immunology; Cell Biology