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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)506-510
Number of pages5
JournalNature
Volume553
Issue number7689
DOIs
StatePublished - Jan 25 2018

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Hematopoietic Stem Cells
Mammalian Embryo
Yolk Sac
Embryonic Structures
Mesonephros
Polycomb-Group Proteins
Multipotent Stem Cells
Fetal Hemoglobin
Pluripotent Stem Cells
Gonads
Cell Lineage
Epigenomics
Endothelium
Embryonic Development
Aorta
Mammals
Pregnancy

ASJC Scopus subject areas

  • General

Cite this

Vo, L. T., Kinney, M. A., Liu, X., Zhang, Y., Barragan, J., Sousa, P. M., ... Daley, G. Q. (2018). Regulation of embryonic haematopoietic multipotency by EZH1. Nature, 553(7689), 506-510. https://doi.org/10.1038/nature25435

Regulation of embryonic haematopoietic multipotency by EZH1. / 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; Daley, George Q.

In: Nature, Vol. 553, No. 7689, 25.01.2018, p. 506-510.

Research output: Contribution to journalArticle

Vo, LT, Kinney, MA, Liu, X, Zhang, Y, Barragan, J, Sousa, PM, Jha, DK, Han, A, Cesana, M, Shao, Z, North, TE, Orkin, SH, Doulatov, S, Xu, J & Daley, GQ 2018, 'Regulation of embryonic haematopoietic multipotency by EZH1', Nature, vol. 553, no. 7689, pp. 506-510. https://doi.org/10.1038/nature25435
Vo LT, Kinney MA, Liu X, Zhang Y, Barragan J, Sousa PM et al. Regulation of embryonic haematopoietic multipotency by EZH1. Nature. 2018 Jan 25;553(7689):506-510. https://doi.org/10.1038/nature25435
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 ; Daley, George Q. / Regulation of embryonic haematopoietic multipotency by EZH1. In: Nature. 2018 ; Vol. 553, No. 7689. pp. 506-510.
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