OpenLB
Open Library of Bioscience
Advanced Search
Nature
01 25, 2018;553 (7689): 506-510.

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
  1. Linda T Vo: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
  2. Melissa A Kinney: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
  3. Xin Liu: Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  4. Yuannyu Zhang: Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  5. Jessica Barragan: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
  6. Patricia M Sousa: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
  7. Deepak K Jha: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
  8. Areum Han: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
  9. Marcella Cesana: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
  10. 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.
  11. Trista E North: Department of Pathology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts, USA.
  12. Stuart H Orkin: Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, USA.
  13. Sergei Doulatov: Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA.
  14. Jian Xu: Children's Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
  15. George Q Daley: Stem Cell Program, Boston Children's Hospital, Boston, Massachusetts, USA.
PMID: 29342143 DOI: 10.1038/nature25435

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.

References

Development. 2011 Mar;138(6):1017-31 [PMID: 21343360]
Immunity. 1994 Jul;1(4):291-301 [PMID: 7889417]
Nature. 2008 Jan 10;451(7175):141-6 [PMID: 18157115]
Nature. 2017 May 25;545(7655):432-438 [PMID: 28514439]
J Exp Med. 2011 Jun 6;208(6):1305-15 [PMID: 21624936]
Dev Cell. 2016 Jan 11;36(1):9-23 [PMID: 26766440]
Nat Genet. 2009 Sep;41(9):1006-10 [PMID: 19684604]
PLoS Biol. 2008 Apr 15;6(4):e93 [PMID: 18416604]
Blood. 1997 Mar 15;89(6):2176-83 [PMID: 9058742]
Cell. 2014 Aug 14;158(4):903-915 [PMID: 25126793]
Mol Cell. 2008 Nov 21;32(4):491-502 [PMID: 19026780]
Nat Biotechnol. 2013 Jan;31(1):46-53 [PMID: 23222703]
Cell. 2006 Apr 21;125(2):315-26 [PMID: 16630819]
Blood. 2015 Jul 9;126(2):167-75 [PMID: 26036803]
Cell. 2007 Jan 26;128(2):325-39 [PMID: 17254970]
Immunity. 2002 May;16(5):661-72 [PMID: 12049718]
Nat Immunol. 2013 Jul;14(7):756-63 [PMID: 23708252]
Genome Biol. 2008;9(9):R137 [PMID: 18798982]
Blood. 2003 Aug 1;102(3):906-15 [PMID: 12702499]
Cell Stem Cell. 2013 Nov 7;13(5):535-48 [PMID: 24054998]
Nat Chem Biol. 2016 Sep;12 (9):672-9 [PMID: 27376689]
Cell Stem Cell. 2013 Oct 3;13(4):459-70 [PMID: 24094326]
Nat Immunol. 2008 Feb;9(2):129-36 [PMID: 18204427]
Genome Biol. 2009;10(3):R25 [PMID: 19261174]
Cell. 2008 Feb 22;132(4):631-44 [PMID: 18295580]
Nat Cell Biol. 2015 May;17(5):580-91 [PMID: 25915127]
Cell Rep. 2015 Jun 30;11(12):1892-904 [PMID: 26095363]
Cold Spring Harb Protoc. 2009 Feb;2009(2):pdb.prot5156 [PMID: 20147086]
Cell Stem Cell. 2014 Jan 2;14(1):68-80 [PMID: 24239285]
Nature. 2012 Mar 04;483(7391):598-602 [PMID: 22388813]
Nature. 2010 Mar 4;464(7285):116-20 [PMID: 20154729]
Nat Rev Immunol. 2011 Jun 10;11(7):478-88 [PMID: 21660052]
Cell. 2014 Apr 24;157(3):549-64 [PMID: 24766805]
Mol Cell. 2008 Nov 21;32(4):503-18 [PMID: 19026781]
Nat Protoc. 2009;4(4):506-17 [PMID: 19325547]
Nat Methods. 2013 Dec;10(12):1213-8 [PMID: 24097267]
Nat Commun. 2012 Jan 10;3:623 [PMID: 22233633]
Mol Cell. 2015 Jan 22;57(2):304-316 [PMID: 25578878]
Blood. 2015 Feb 26;125(9):1418-26 [PMID: 25587036]
Immunity. 2000 Oct;13(4):423-31 [PMID: 11070161]

Grants

  1. K99 HL123484/NHLBI NIH HHS
  2. R24 OD017870/NIH HHS
  3. U01 HL134812/NHLBI NIH HHS
  4. R01 DK098241/NIDDK NIH HHS
  5. P30 DK049216/NIDDK NIH HHS
  6. U01 HL100001/NHLBI NIH HHS
  7. U54 DK110805/NIDDK NIH HHS
  8. R24 DK092760/NIDDK NIH HHS
  9. /Howard Hughes Medical Institute
  10. R01HL04880/NHLBI NIH HHS
  11. K01 DK093543/NIDDK NIH HHS
  12. R00 HL123484/NHLBI NIH HHS
  13. R01 DK111430/NIDDK NIH HHS

MeSH Term

Animals
Cell Differentiation
Cell Lineage
Chromatin
Embryonic Development
Embryonic Stem Cells
Female
Gene Silencing
Hematopoiesis
Hematopoietic Stem Cells
Humans
Lymphocytes
Mice
Multipotent Stem Cells
Pluripotent Stem Cells
Polycomb Repressive Complex 2

Chemicals

Chromatin
EZH1 protein, human
Ezh1 protein, mouse
Polycomb Repressive Complex 2
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Word Cloud

Similar Articles

Cited By