Letter | Published:

Regulation of embryonic haematopoietic multipotency by EZH1

Nature volume 553, pages 506510 (25 January 2018) | Download Citation

Abstract

All haematopoietic cell lineages that circulate in the blood of adult mammals derive from multipotent haematopoietic stem cells (HSCs)1. By contrast, in the blood of mammalian embryos, lineage-restricted progenitors arise first, independently of HSCs, which only emerge later in gestation2,3. As best defined in the mouse, ‘primitive’ progenitors first appear in the yolk sac at 7.5 days post-coitum2,3. Subsequently, erythroid–myeloid progenitors that express fetal haemoglobin4, as well as fetal lymphoid progenitors5, 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 vasculature3. 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 silencing6, 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.

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Acknowledgements

We thank T. Jenuwein for sharing the Ezh1 mutant mice, which were generated at the Research Institute of Molecular Pathology (IMP, Vienna) in 2000 by D. O’Carroll (laboratory of T. Jenuwein) with the help of M. Sibilia (laboratory of E. Wagner). We also thank T. Schlaeger and the hESC Core Facility at Boston Children’s Hospital for providing pluripotent stem-cell lines, R. Mathieu from BCH Flow Cytometry Core, and M. J. Chen for technical advice. This work was supported by grants from the NIH NIDDK (R24-DK092760, R24-DK49216) and NHLBI Progenitor Cell Biology Consortium (U01-HL100001); NHLBI R01HL04880 and NIH R24OD017870-01. L.T.V. is supported by the NSF Graduate Research Fellowship. M.A.K. is supported by T32 NIH Training Grant from BWH Hematology. M.C. is supported by a fellowship from the Leukemia and Lymphoma Society. S.D. is supported by K99 NIH NHLBI award (1K99HL123484). S.H.O. is an Investigator of the Howard Hughes Medical Institute. J.X. is supported by NIH grants (K01DK093543 and R01DK111430) and a Cancer Prevention and Research Institute of Texas (CPRIT) New Investigator award (RR140025). G.Q.D. was supported by the Howard Hughes Medical Institute, and is an associate member of the Broad Institute and an investigator of the Manton Center for Orphan Disease Research.

Author information

Affiliations

  1. Stem Cell Program, Boston Children’s Hospital, Boston, Massachusetts, USA

    • Linda T. Vo
    • , Melissa A. Kinney
    • , Jessica Barragan
    • , Patricia M. Sousa
    • , Deepak K. Jha
    • , Areum Han
    • , Marcella Cesana
    •  & George Q. Daley
  2. Division of Hematology/Oncology, Boston Children’s Hospital and Dana Farber Cancer Institute, Boston, Massachusetts, USA

    • Linda T. Vo
    • , Melissa A. Kinney
    • , Jessica Barragan
    • , Patricia M. Sousa
    • , Deepak K. Jha
    • , Areum Han
    • , Marcella Cesana
    • , Stuart H. Orkin
    •  & George Q. Daley
  3. Harvard Medical School, Boston, Massachusetts, USA

    • Linda T. Vo
    • , Stuart H. Orkin
    •  & George Q. Daley
  4. Children’s Medical Center Research Institute, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    • Xin Liu
    • , Yuannyu Zhang
    •  & Jian Xu
  5. Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

    • Yuannyu Zhang
    •  & Zhen Shao
  6. Department of Pathology, Beth Israel-Deaconess Medical Center, Boston, Massachusetts, USA

    • Trista E. North
  7. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    • Stuart H. Orkin
  8. Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA

    • Sergei Doulatov

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Contributions

L.T.V., S.D. and G.Q.D. conceived the project. L.T.V. designed all experiments, performed all pluripotent stem-cell and mouse transplantation studies and interpreted data. M.A.K. analysed RNA-seq, ChIP–seq and ATAC–seq data, performed all network analyses and interpreted data. X.L. performed ChIP–seq and ATAC–seq experiments. Y.Z. and Z.S. analysed ChIP–seq and ATAC–seq data. J.B. performed and analysed qPCR and western blot validations, assisted with tissue culture, animal dissections and mouse transplantation studies. P.M.S. assisted with timed matings, animal dissections and mouse transplantation studies. D.K.J. performed western blot validations, cloned the Ezh2-mCherry overexpression construct, assisted with ChIP–seq optimization and interpreted data. M.C. assisted with ChIP–seq optimization. A.H. assisted with RNA-seq analysis. T.E.N., S.H.O., S.D., J.X. and G.Q.D. supervised research, interpreted data and participated in project planning. L.T.V., T.E.N., S.D. and G.Q.D. wrote the manuscript with input from all co-authors.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to George Q. Daley.

Reviewer Information Nature thanks B. Gottgens, H. Mikkola and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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