Pluto Bioinformatics

GSE130904: Loss of the epigenetic modifierSetd2and H3K36me3 impairs non-homologous end-joining in lymphogenesis and neurogenesis

Bulk RNA sequencing

The resolution and repair of DNA double stranded breaks (DSB) in normal, early lymphocyte and post- mitotic, central nervous system (CNS) development is dependent on non-homologous end-joining (NHEJ) (1-5). Understanding of this phenomenon in lymphogenesis has primarily centered on the study of RAG1/2 recombinases and classical NHEJ factors (cNHEJ) (1-3). Loss or defects of these core factors can impair end-processing (DNA-PKCs complex, ARTEMIS) or end-joining (KU proteins, XRCC4, XLF, LIG4) and have been described as drivers of diseases characterized by severe immunodeficiencies in both mouse models and in human disease (1-8). The ataxia telangiectasia-mutated protein (ATM), that phosphorylates targets such as histone H2AX to activate and recruit members of DDR, is also involved in the end-ligation process through the stabilization of a post-cleavage complex of VDJ intermediates (9-11). Loss of ATM, H2AX, or even XLF alone, however, has only modest effects on lymphogenesis and VDJ recombination remains largely competent (9-12). While several aspects of early B cell development that are under epigenetic regulation have been described (13-15), little has been described in terms of a critical role for chromatin modifications on the cNHEJ-mediated recombination process. Here, we show critical role for histone H3 lysine methyltransferase Setd2 and its modification of lysine-36 tri-methylation (H3K36me3) in the proper joining of DNA ends during VDJ recombination in a genetically engineered mouse model. Loss of Setd2 and H3K36me3 profoundly blocks lymphogenesis due to aberrant end- joining of recombination products and leads to an overall reduction of immune repertoire. Combined Setd2 and ATM deficiency further impairs cNHEJ, suggesting overlapping functions of Setd2/H3K36me3 and ATM in preventing aberrant recombination. We further validated the role of Setd2/H3K36me3 in NHEJ in early neuronal development, where loss resulted in apoptosis and embryonic lethality of early post-mitotic neurons. Together, these studies indicate a broader and essential role of Setd2/H3K36me3 in cNHEJ and developmental processes. SOURCE: Richard Koche (kocher@mskcc.org) - Memorial Sloan Kettering Cancer Center