Regulation of embryonic haematopoietic multipotency by EZH1.
Linda T Vo, Melissa A Kinney, Xin Liu, Yuannyu Zhang, Jessica Barragan, Patricia M Sousa, Deepak K Jha, Areum Han, Marcella Cesana, Zhen Shao, Trista E North, Stuart H Orkin, Sergei Doulatov, Jian Xu, George Q Daley
Author Information
Linda T Vo: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
Melissa A Kinney: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
Xin Liu: Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Yuannyu Zhang: Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Jessica Barragan: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
Patricia M Sousa: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
Deepak K Jha: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
Areum Han: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
Marcella Cesana: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
Zhen Shao: Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Trista E North: Department of Pathology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts, USA.
Stuart H Orkin: Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Sergei Doulatov: Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA.
Jian Xu: Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
George Q Daley: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
All haematopoietic cell lineages that circulate in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs). By contrast, in the blood of mammalian embryos, lineage-restricted progenitors arise first, independently of HSCs, which only emerge later in gestation. As best defined in the mouse, 'primitive' progenitors first appear in the yolk sac at 7.5 days post-coitum. Subsequently, erythroid-myeloid progenitors that express fetal haemoglobin, as well as fetal lymphoid progenitors, develop in the yolk sac and the embryo proper, but these cells lack HSC potential. Ultimately, 'definitive' HSCs with long-term, multilineage potential and the ability to engraft irradiated adults emerge at 10.5 days post-coitum from arterial endothelium in the aorta-gonad-mesonephros and other haemogenic vasculature. The molecular mechanisms of this reverse progression of haematopoietic ontogeny remain unexplained. We hypothesized that the definitive haematopoietic program might be actively repressed in early embryogenesis through epigenetic silencing, and that alleviating this repression would elicit multipotency in otherwise lineage-restricted haematopoietic progenitors. Here we show that reduced expression of the Polycomb group protein EZH1 enhances multi-lymphoid output from human pluripotent stem cells. In addition, Ezh1 deficiency in mouse embryos results in precocious emergence of functional definitive HSCs in vivo. Thus, we identify EZH1 as a repressor of haematopoietic multipotency in the early mammalian embryo.
