Abstract
DOT1L methylates histone H3K79 and is aberrantly regulated in MLL‐rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L 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 HDAC1 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 DOT1L dosage. Furthermore, cell lines derived from Hdac1Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.
Highlights
Aberrant histone modification patterns have been observed in many diseases and this deregulation of chromatin can play a causative role in disease
Since higher Dot1 activity in yeast leads to a shift from lower to higher methylation states (Frederiks et al 2008), the H3K79me3 over H3K79me1 ratio was used as a measure for Dot1 activity
We describe that the yeast histone deacetylase (HDAC), Rpd3, is a negative regulator of H3K79 methylation that restricts methylation at the 5’ ends of its target genes
Summary
Aberrant histone modification patterns have been observed in many diseases and this deregulation of chromatin can play a causative role in disease. The histone H3K79 methyltransferase DOT1L (KMT4; Dot in yeast) is an epigenetic enzyme for which inhibitors are in clinical development for the treatment of MLL‐rearranged (MLL‐r) leukemia (Stein and Tallman 2016). In MLL‐r leukemia, DOT1L recruitment to MLL target genes, such as the HoxA cluster leads to aberrant H3K79 methylation and increased transcription (reviewed in Vlaming and Van. Leeuwen 2016). The DOT1L inhibitor Pinometostat (EPZ‐5676) has shown promising results in the lab and is currently in clinical development (Bernt et al 2011; Daigle et al 2013; Waters et al.2015; Stein and Tallman 2016; Stein et al 2018), the cellular mechanisms and consequences of DOT1L deregulation are only just being uncovered (Vlaming and Van Leeuwen 2016)
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