Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis

Abstract

Polycomb repressive complex (PRC) 1 regulates stem cell fate by mediating mono-ubiquitination of histone H2A at lysine 119. While canonical PRC1 is critical for hematopoietic stem and progenitor cell (HSPC) maintenance, the role of non-canonical PRC1 in hematopoiesis remains elusive. PRC1.1, a non-canonical PRC1, consists of PCGF1, RING1B, KDM2B, and BCOR. We recently showed that PRC1.1 insufficiency induced by the loss of PCGF1 or BCOR causes myeloid-biased hematopoiesis and promotes transformation of hematopoietic cells in mice. Here we show that PRC1.1 serves as an epigenetic switch that coordinates homeostatic and emergency hematopoiesis. PRC1.1 maintains balanced output of steady-state hematopoiesis by restricting C/EBPa-dependent precocious myeloid differentiation of HSPCs and the HOXA9- and β-catenin-driven self-renewing network in myeloid progenitors. Upon regeneration, PRC1.1 is transiently inhibited to facilitate formation of granulocyte-macrophage progenitor (GMP) clusters, thereby promoting emergency myelopoiesis. Moreover, constitutive inactivation of PRC1.1 results in unchecked expansion of GMPs and eventual transformation. Collectively, our results define PRC1.1 as a novel critical regulator of emergency myelopoiesis, dysregulation of which leads to myeloid transformation.

Data availability

RNA sequence, ChIP sequence and ATAC sequence data were deposited in the DDBJ (accession number DRA008518 and DRA013523).

The following data sets were generated

Article and author information

Author details

  1. Yaeko Nakajima-Takagi

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Motohiko Oshima

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Junichiro Takano

    Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Shuhei Koide

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  5. Naoki Itokawa

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  6. Shun Uemura

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1520-6808
  7. Masayuki Yamashita

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9459-4329
  8. Shohei Andoh

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  9. Kazumasa Aoyama

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  10. Yusuke Isshiki

    Department of Cellular and Molecular Medicine, Chiba University, Chiba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  11. Daisuke Shinoda

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  12. Atsunori Saraya

    Department of Cellular and Molecular Medicine, Chiba University, Chiba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  13. Fumio Arai

    Department of Stem Cell Biology and Medicine, Kyushu University, Fukuoka, Japan
    Competing interests
    The authors declare that no competing interests exist.
  14. Kiyoshi Yamaguchi

    Division of Clinical Genome Research, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
  15. Yoichi Furukawa

    Division of Clinical Genome Research, University of Tokyo, Tokyo, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0462-8631
  16. Haruhiko Koseki

    Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8424-5854
  17. Tomokatsu Ikawa

    Division of Immunobiology, Tokyo University of Science, Chiba, Japan
    Competing interests
    The authors declare that no competing interests exist.
  18. Atsushi Iwama

    Division of Stem Cell and Molecular Medicine, University of Tokyo, Tokyo, Japan
    For correspondence
    03aiwama@ims.u-tokyo.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9410-8992

Funding

Japan Society for the Promotion of Science (19H05653)

  • Atsushi Iwama

Japan Society for the Promotion of Science (20K08728)

  • Yaeko Nakajima-Takagi

Japan Society for the Promotion of Science (19H05746)

  • Atsushi Iwama

Japan Agency for Medical Research and Development (21zf0127003h0001)

  • Atsushi Iwama

Japan Agency for Medical Research and Development (JP223fa627001)

  • Atsushi Iwama

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yelena Ginzburg, Icahn School of Medicine at Mount Sinai, United States

Ethics

Animal experimentation: All experiments using mice were performed in accordance with our institutional guidelines for the use of laboratory animals and approved by the Review Board for Animal Experiments of Chiba University (approval ID: 30-56) and the University of Tokyo (approval ID: PA18-03).

Version history

  1. Received: August 26, 2022
  2. Preprint posted: September 8, 2022 (view preprint)
  3. Accepted: June 1, 2023
  4. Accepted Manuscript published: June 2, 2023 (version 1)
  5. Version of Record published: June 22, 2023 (version 2)

Copyright

© 2023, Nakajima-Takagi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yaeko Nakajima-Takagi
  2. Motohiko Oshima
  3. Junichiro Takano
  4. Shuhei Koide
  5. Naoki Itokawa
  6. Shun Uemura
  7. Masayuki Yamashita
  8. Shohei Andoh
  9. Kazumasa Aoyama
  10. Yusuke Isshiki
  11. Daisuke Shinoda
  12. Atsunori Saraya
  13. Fumio Arai
  14. Kiyoshi Yamaguchi
  15. Yoichi Furukawa
  16. Haruhiko Koseki
  17. Tomokatsu Ikawa
  18. Atsushi Iwama
(2023)
Polycomb repressive complex 1.1 coordinates homeostatic and emergency myelopoiesis
eLife 12:e83004.
https://doi.org/10.7554/eLife.83004

Share this article

https://doi.org/10.7554/eLife.83004

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