Inducible histone K-to-M mutations are dynamic tools to probe the physiological role of site-specific histone methylation in vitro and in vivo

Nat Cell Biol. 2019 Nov;21(11):1449-1461. doi: 10.1038/s41556-019-0403-5. Epub 2019 Oct 28.


Development and differentiation are associated with profound changes to histone modifications, yet their in vivo function remains incompletely understood. Here, we generated mouse models expressing inducible histone H3 lysine-to-methionine (K-to-M) mutants, which globally inhibit methylation at specific sites. Mice expressing H3K36M developed severe anaemia with arrested erythropoiesis, a marked haematopoietic stem cell defect, and rapid lethality. By contrast, mice expressing H3K9M survived up to a year and showed expansion of multipotent progenitors, aberrant lymphopoiesis and thrombocytosis. Additionally, some H3K9M mice succumbed to aggressive T cell leukaemia/lymphoma, while H3K36M mice exhibited differentiation defects in testis and intestine. Mechanistically, induction of either mutant reduced corresponding histone trimethylation patterns genome-wide and altered chromatin accessibility as well as gene expression landscapes. Strikingly, discontinuation of transgene expression largely restored differentiation programmes. Our work shows that individual chromatin modifications are required at several specific stages of differentiation and introduces powerful tools to interrogate their roles in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Transplantation
  • Cell Lineage / genetics
  • Disease Models, Animal
  • Doxycycline / pharmacology
  • Epigenesis, Genetic*
  • Erythroid Cells / metabolism
  • Erythroid Cells / pathology
  • Female
  • Granulocytes / metabolism
  • Granulocytes / pathology
  • Histones / genetics
  • Histones / metabolism*
  • Leukemia, T-Cell / chemically induced
  • Leukemia, T-Cell / genetics*
  • Leukemia, T-Cell / metabolism
  • Leukemia, T-Cell / pathology
  • Lysine / metabolism*
  • Male
  • Methionine / metabolism*
  • Methylation
  • Mice
  • Mice, Transgenic
  • Mouse Embryonic Stem Cells / metabolism
  • Mouse Embryonic Stem Cells / pathology
  • Mutation
  • Signal Transduction
  • Survival Analysis
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / pathology
  • Teratoma / chemically induced
  • Teratoma / genetics*
  • Teratoma / metabolism
  • Teratoma / pathology


  • Histones
  • Methionine
  • Lysine
  • Doxycycline