DOT
1L methylates histone H3K79 and is aberrantly regulated in
MLL
‐rearranged leukemia. Inhibitors have been developed to target
DOT
1L activity in leukemia, but cellular mechanisms that regulate
DOT
1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog
HDAC
1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of
Hdac1
retained the increased H3K79 methylation and were sensitive to reduced
DOT
1L dosage. Furthermore, cell lines derived from
Hdac1
Δ/Δ
thymic lymphomas were sensitive to a
DOT
1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between
HDAC
1 and
DOT
1L with impact in murine thymic lymphoma development.
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 toward a memory-like state, independent of antigen exposure and in a cell-intrinsic manner. Mechanistically, DOT1L controlled CD8+ T cell differentiation by ensuring normal T cell receptor density and signaling. DOT1L also maintained epigenetic identity, in part by indirectly supporting the repression of developmentally regulated genes. Finally, deletion of Dot1L in T cells resulted in an impaired immune response. 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 controlling epigenetic integrity.
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