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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.
Introduction
Fetal hematopoietic stem cells (HSCs) proliferate rapidly and contribute to massive expansion of the HSC pool (1, 2). In contrast, adult HSCs divide rarely in steady-state conditions, as a majority of cells reside in the quiescent G0 phase of the cell cycle and return to quiescence after periods of proliferation (3-8). In mice, transition from the fetal/neonatal to the adult HSC program occurs in the bone marrow (BM) niche within weeks after birth and coincides with establishment of HSC quiescence, functional and phenotypic changes, and downregulated expression of the transcription factor Sox17 and other fetal HSC genes (1, 9-12). Failure to establish or maintain quiescence has been linked to adult HSC depletion, increased sensitivity to myeloablation, and reduced engraftment in transplantation assays (1, 13-16). However, the regulatory mechanisms controlling quiescence and successful initiation of the adult HSC program in the BM remain poorly understood.
The trithorax group (TrxG) is a diverse family of epigenetic regulators originally identified to control body patterning in Drosophila (17). In flies, individual TrxG members cooperate to promote expression of homeobox (Hox) genes, and combined heterozygous TrxG gene mutations act as dominant enhancers of one another (18, 19). Mixed-lineage leukemia 1 (Mll1) is the trithorax homolog and founding TrxG member in...