UTX maintains the functional integrity of the murine hematopoietic system by globally regulating aging-associated genes

Blood. 2021 Feb 18;137(7):908-922. doi: 10.1182/blood.2019001044.


Epigenetic regulation is essential for the maintenance of the hematopoietic system, and its deregulation is implicated in hematopoietic disorders. In this study, UTX, a demethylase for lysine 27 on histone H3 (H3K27) and a component of COMPASS-like and SWI/SNF complexes, played an essential role in the hematopoietic system by globally regulating aging-associated genes. Utx-deficient (UtxΔ/Δ) mice exhibited myeloid skewing with dysplasia, extramedullary hematopoiesis, impaired hematopoietic reconstituting ability, and increased susceptibility to leukemia, which are the hallmarks of hematopoietic aging. RNA-sequencing (RNA-seq) analysis revealed that Utx deficiency converted the gene expression profiles of young hematopoietic stem-progenitor cells (HSPCs) to those of aged HSPCs. Utx expression in hematopoietic stem cells declined with age, and UtxΔ/Δ HSPCs exhibited increased expression of an aging-associated marker, accumulation of reactive oxygen species, and impaired repair of DNA double-strand breaks. Pathway and chromatin immunoprecipitation analyses coupled with RNA-seq data indicated that UTX contributed to hematopoietic homeostasis mainly by maintaining the expression of genes downregulated with aging via demethylase-dependent and -independent epigenetic programming. Of note, comparison of pathway changes in UtxΔ/Δ HSPCs, aged muscle stem cells, aged fibroblasts, and aged induced neurons showed substantial overlap, strongly suggesting common aging mechanisms among different tissue stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Animals
  • Cellular Senescence / genetics
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Female
  • Gene Expression Regulation / genetics*
  • Genetic Predisposition to Disease
  • Hematopoiesis / genetics*
  • Hematopoiesis, Extramedullary
  • Hematopoietic System / physiology*
  • Histone Code / genetics*
  • Histone Demethylases / deficiency
  • Histone Demethylases / genetics
  • Histone Demethylases / physiology*
  • Immune Reconstitution
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Leukemia, Experimental / genetics
  • Leukemia, Experimental / virology
  • Male
  • Mice
  • Mice, Knockout
  • Moloney murine leukemia virus / physiology
  • Myeloid Cells / pathology
  • Radiation Chimera
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / metabolism
  • Transcription Factors / metabolism
  • Virus Integration


  • Reactive Oxygen Species
  • Recombinant Proteins
  • Transcription Factors
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • Utx protein, mouse
  • Kdm6b protein, mouse