Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells.
| Publication Type | Academic Article |
| Authors | Jones M, Chase J, Brinkmeier M, Xu J, Weinberg D, Schira J, Friedman A, Malek S, Grembecka J, Cierpicki T, Dou Y, Camper S, Maillard I |
| Journal | J Clin Invest |
| Volume | 125 |
| Issue | 5 |
| Pagination | 2007-20 |
| Date Published | 04/13/2015 |
| ISSN | 1558-8238 |
| Keywords | Hematopoiesis, Hematopoietic Stem Cells, Histone-Lysine N-Methyltransferase |
| 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. |
| DOI | 10.1172/JCI78124 |
| PubMed ID | 25866973 |
| PubMed Central ID | PMC4463197 |