Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells

J Clin Invest. 2015 May;125(5):2007-20. doi: 10.1172/JCI78124. Epub 2015 Apr 13.

Abstract

Rapidly cycling fetal and neonatal hematopoietic stem cells (HSCs) generate a pool of quiescent adult HSCs after establishing hematopoiesis in the bone marrow. We report an essential role for the trithorax group gene absent, small, or homeotic 1-like (Ash1l) at this developmental transition. Emergence and expansion of Ash1l-deficient fetal/neonatal HSCs were preserved; however, in young adult animals, HSCs were profoundly depleted. Ash1l-deficient adult HSCs had markedly decreased quiescence and reduced cyclin-dependent kinase inhibitor 1b/c (Cdkn1b/1c) expression and failed to establish long-term trilineage bone marrow hematopoiesis after transplantation to irradiated recipients. Wild-type HSCs could efficiently engraft when transferred to unirradiated, Ash1l-deficient recipients, indicating increased availability of functional HSC niches in these mice. Ash1l deficiency also decreased expression of multiple Hox genes in hematopoietic progenitors. Ash1l cooperated functionally with mixed-lineage leukemia 1 (Mll1), as combined loss of Ash1l and Mll1, but not isolated Ash1l or Mll1 deficiency, induced overt hematopoietic failure. Our results uncover a trithorax group gene network that controls quiescence, niche occupancy, and self-renewal potential in adult HSCs.

Publication types

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

MeSH terms

  • Anemia, Aplastic
  • Animals
  • Animals, Newborn
  • Bone Marrow Diseases
  • Bone Marrow Failure Disorders
  • Bone Marrow Transplantation
  • Cell Cycle / genetics
  • Cell Division / genetics
  • Colony-Forming Units Assay
  • DNA-Binding Proteins
  • Fluorouracil / toxicity
  • Gene Expression Regulation, Developmental
  • Graft Survival
  • Hematopoiesis / genetics
  • Hematopoiesis / physiology*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism
  • Hemoglobinuria, Paroxysmal / genetics
  • Hemoglobinuria, Paroxysmal / pathology
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / physiology*
  • Liver / cytology
  • Liver / embryology
  • Liver / metabolism
  • Liver Transplantation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Multipotent Stem Cells / cytology
  • Myeloid-Lymphoid Leukemia Protein / deficiency
  • Myeloid-Lymphoid Leukemia Protein / physiology
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / physiology
  • Radiation Chimera
  • Stem Cell Niche

Substances

  • DNA-Binding Proteins
  • Men1 protein, mouse
  • Proto-Oncogene Proteins
  • Myeloid-Lymphoid Leukemia Protein
  • Ash1l protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse
  • Fluorouracil

Supplementary concepts

  • Bone Marrow failure syndromes