Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma

EMBO J. 2019 Jul 15;38(14):e101564. doi: 10.15252/embj.2019101564. Epub 2019 Jun 17.


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.

Keywords: Chromatin; H3K79 methylation; histone acetylation; histone ubiquitination; lymphoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • Cell Line, Tumor
  • Gene Deletion
  • Histone Deacetylase 1 / genetics*
  • Histone Deacetylase 2 / metabolism*
  • Histone Deacetylases / genetics
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histones / metabolism*
  • Humans
  • Lymphoma / genetics
  • Lymphoma / metabolism*
  • Methylation
  • Mice
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Thymus Neoplasms / genetics
  • Thymus Neoplasms / metabolism*


  • Histones
  • Saccharomyces cerevisiae Proteins
  • DOT1L protein, human
  • Histone-Lysine N-Methyltransferase
  • RPD3 protein, S cerevisiae
  • HDAC1 protein, human
  • HDAC2 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Histone Deacetylases

Associated data

  • GEO/GSE107331
  • GEO/GSE67151
  • GEO/GSE52000