title: Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells.
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.
authors: Morgan
authors: M
authors: Jones
authors: Jennifer
authors: J
authors: Chase
authors: Michelle
authors: M
authors: Brinkmeier
authors: Jing
authors: J
authors: Xu
authors: Daniel N
authors: DN
authors: Weinberg
authors: Julien
authors: J
authors: Schira
authors: Ann
authors: A
authors: Friedman
authors: Sami
authors: S
authors: Malek
authors: Jolanta
authors: J
authors: Grembecka
authors: Tomasz
authors: T
authors: Cierpicki
authors: Yali
authors: Y
authors: Dou
authors: Sally A
authors: SA
authors: Camper
authors: Ivan
authors: I
authors: Maillard
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D000831:Animals, Newborn; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D016026:Bone Marrow Transplantation; D002453:Cell Cycle / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D003114:Colony-Forming Units Assay; D004268:DNA-Binding Proteins; D005472:Fluorouracil / Q000633:toxicity; D018507:Gene Expression Regulation, Developmental; D006085:Graft Survival; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D016031:Liver Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D039902:Multipotent Stem Cells / Q000166:cytology; D051788:Myeloid-Lymphoid Leukemia Protein / Q000172:deficiency / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000502:physiology; D011828:Radiation Chimera; D055153:Stem Cell Niche
chemical_list: D004268:DNA-Binding Proteins; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; C000600280:Ash1l protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D005472:Fluorouracil