1. Regulation of embryonic haematopoietic multipotency by EZH1
- Author
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Zhen Shao, Patricia Sousa, Linda T. Vo, Trista E. North, George Q. Daley, Stuart H. Orkin, Jessica Barragan, Deepak Kumar Jha, Sergei Doulatov, Melissa A. Kinney, Yuannyu Zhang, Areum Han, Jian Xu, Marcella Cesana, Xin Liu, Vo, Linda T., Kinney, Melissa A., Liu, Xin, Zhang, Yuannyu, Barragan, Jessica, Sousa, Patricia M., Jha, Deepak K., Han, Areum, Cesana, Marcella, Shao, Zhen, North, Trista E., Orkin, Stuart H., Doulatov, Sergei, Xu, Jian, and Daley, George Q.
- Subjects
Pluripotent Stem Cells ,0301 basic medicine ,Cellular differentiation ,Embryonic Development ,Biology ,Mice ,03 medical and health sciences ,Embryonic Stem Cell ,medicine ,Animals ,Humans ,Cell Lineage ,Hematopoiesi ,Lymphocytes ,Gene Silencing ,Progenitor cell ,Yolk sac ,Induced pluripotent stem cell ,Embryonic Stem Cells ,Multipotent Stem Cell ,Pluripotent Stem Cell ,Multidisciplinary ,Animal ,Multipotent Stem Cells ,Polycomb Repressive Complex 2 ,Cell Differentiation ,Hematopoietic Stem Cell ,Hematopoietic Stem Cells ,Embryonic stem cell ,Chromatin ,Hematopoiesis ,Cell biology ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,embryonic structures ,Female ,Lymphocyte ,Stem cell ,Human - Abstract
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.
- Published
- 2018