RT Journal Article SR Electronic T1 The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8+ T cells JF bioRxiv FD Cold Spring Harbor Laboratory SP 826255 DO 10.1101/826255 A1 Eliza Mari Kwesi-Maliepaard A1 Muhammad Assad Aslam A1 Mir Farshid Alemdehy A1 Teun van den Brand A1 Chelsea McLean A1 Hanneke Vlaming A1 Tibor van Welsem A1 Tessy Korthout A1 Cesare Lancini A1 Sjoerd Hendriks A1 Tomasz Ahrends A1 Dieke van Dinther A1 Joke M.M. den Haan A1 Jannie Borst A1 Elzo de Wit A1 Fred van Leeuwen A1 Heinz Jacobs YR 2019 UL http://biorxiv.org/content/early/2019/11/18/826255.abstract AB Cytotoxic T-cell differentiation is guided by epigenome adaptations but how epigenetic mechanisms control lymphocyte development has not been well defined. Here we show that the histone methyltransferase DOT1L, which marks the nucleosome core on active genes, safeguards normal differentiation of CD8+ T cells. T-cell specific ablation of Dot1L resulted in loss of naïve CD8+ T cells and premature differentiation towards a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Without DOT1L, the memory-like CD8+ cells fail to acquire full effector functions in vitro and in vivo. Mechanistically, DOT1L controlled T-cell differentiation and function by ensuring normal T-cell receptor density and signaling, and by maintaining epigenetic identity, in part by indirectly supporting the repression of developmentally-regulated genes. Through our study DOT1L is emerging as a central player in physiology of CD8+ T cells, acting as a barrier to prevent premature differentiation and supporting the licensing of the full effector potential of cytotoxic T cells.