TY - JOUR T1 - Evolutionarily-conserved chromatin crosstalk generates a DOT1L-dose dependency in thymic lymphoma caused by loss of HDAC1 JF - bioRxiv DO - 10.1101/509976 SP - 509976 AU - Hanneke Vlaming AU - Chelsea M. McLean AU - Tessy Korthout AU - Mir Farshid Alemdehy AU - Sjoerd Hendriks AU - Cesare Lancini AU - Sander Palit AU - Sjoerd Klarenbeek AU - Eliza Mari Kwesi-Maliepaard AU - Thom M. Molenaar AU - Liesbeth Hoekman AU - Thierry T. Schmidlin AU - A.F. Maarten Altelaar AU - Tibor van Welsem AU - Jan-Hermen Dannenberg AU - Heinz Jacobs AU - Fred van Leeuwen Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/01/10/509976.abstract N2 - DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia but the cellular mechanisms that regulate DOT1L are still poorly understood. Here we identify the budding yeast histone deacetylase Rpd3 as a negative regulator of 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 DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily-conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development. ER -