The Lysine Histone Methyltransferase SETD2Is Required for Appropriate Immunoglobulin VDJ Recombination

Rearrangement of the immunoglobulin heavy chain locus (IgH) through non-homologous end-joining (NHEJ)-mediated VDJ recombination is a requisite step in normal lymphocyte development. This process is initiated through cleavage of DNA by RAG1/2recombinases and repair by classical NHEJ pathway factors. Loss or defects of these factors can impair end-processing (DNA-PKcs, ARTEMIS) or end-ligation (KU70/80, XRCC4, XLF, LIGIV) of rearrangement and are drivers of disease, notably, severe combined immunodeficiency (SCID). In addition to these core NHEJ factors, other proteins, such as ATM kinase, have been shown to be critical for the stabilization of the post-cleavage VDJ intermediates to ensure proper signal joint formation. While epigenetic regulation of this process has been described through the maintenance of accessibility for transcription factors and RAG1/2, very little is known about the role of chromatin modifications on NHEJ-mediated VDJ recombination.