TY - JOUR
T1 - Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma
AU - Vlaming, Hanneke
AU - McLean, Chelsea M.
AU - Korthout, Tessy
AU - Alemdehy, Mir Farshid
AU - Hendriks, Sjoerd
AU - Lancini, Cesare
AU - Palit, Sander
AU - Klarenbeek, Sjoerd
AU - Kwesi-Maliepaard, Eliza Mari
AU - Molenaar, Thom M.
AU - Hoekman, Liesbeth
AU - Schmidlin, Thierry T.
AU - Altelaar, A. F. Maarten
AU - van Welsem, Tibor
AU - Dannenberg, Jan-Hermen
AU - Jacobs, Heinz
AU - van Leeuwen, Fred
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85067462981&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31209067
U2 - https://doi.org/10.15252/embj.2019101564
DO - https://doi.org/10.15252/embj.2019101564
M3 - Article
C2 - 31209067
SN - 0261-4189
VL - 38
JO - EMBO Journal
JF - EMBO Journal
IS - 14
M1 - e101564
ER -