The histone methyltransferase DOT1L prevents antigen-independent differentiation and safeguards epigenetic identity of CD8⁺T cells

Abstract

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 cellintrinsic 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.

DOT1L interaction partner AF10 controls patterning of H3K79 methylation and RNA polymerase II to maintain cell identity

“…Perhaps this reduced concentration of EPZ-5676 mimics DOT1L attenuation via ΔAF10 in our study. DOT1L knockout in lymphocytes downregulated EZH2 and de-repressed genes normally shut off by H3K27me3 (Aslam et al, 2021; Kwesi-Maliepaard et al, 2020). Inhibition of DOT1L and EZH2 have both shown promise in pre-clinical MLL-R studies suggesting that H3K79me and H3K27me3 are functionally connected in leukemia (Lenard et al, 2020).…”

DOT1L inhibition enhances pluripotency beyond acquisition of epithelial identity and without immediate suppression of the somatic transcriptome

“…Dot1l KO results in disorganized yolk sacs containing primitive erythrocytes. DOT1L is also necessary for development of the heart (Nguyen and Zhang, 2011), cerebral cortex (Franz et al, 2019), and chondrocytes (Castan ˜o Betancourt et al, 2012) and normal CD8 + T cell differentiation (Kwesi-Maliepaard et al, 2020). H3K79me is not required for pluripotency, as ESCs continue to self-renew in the absence of DOT1L or DOT1L catalytic activity (Barry et al, 2009;Cao et al, 2020;Jones et al, 2008).…”

The Methyltransferase DOT1L Controls Activation and Lineage Integrity in CD4+ T Cells during Infection and Inflammation

“…Based on our gene-expression data and H3K79me2 coverage analysis, we suggest that a subset of highly expressed genes is dependent on the presence of H3K79me2. Although the reason why some genes are dependent on the presence of H3K79me2 and others are not is the subject of ongoing investigations (Kwesi-Maliepaard et al, 2020). In the absence of DOT1L, some genes are significantly downregulated across Th cell subsets in the absence of H3K79me2.…”