1. Developmental Biology
  2. Chromosomes and Gene Expression
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EED orchestration of heart maturation through interaction with HDACs is H3K27me3-independent

  1. Shanshan Ai
  2. Yong Peng
  3. Chen Li
  4. Fei Gu
  5. Xianhong Yu
  6. Yanzhu Yue
  7. Qing Ma
  8. Jinghai Chen
  9. Zhiqiang Lin
  10. Pingzhu Zhou
  11. Huafeng Xie
  12. Terence W Prendiville
  13. Wen Zheng
  14. Yuli Liu
  15. Stuart H Orkin
  16. Da-zhi Wang
  17. Jia Yu
  18. William T Pu  Is a corresponding author
  19. Aibin He  Is a corresponding author
  1. Peking University, China
  2. Boston Children's Hospital, United States
  3. Our Lady's Children's Hospital Crumlin, Ireland
  4. Peking Union Medical College, China
Research Article
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Cite this article as: eLife 2017;6:e24570 doi: 10.7554/eLife.24570

Abstract

In proliferating cells, where most Polycomb repressive complex 2 (PRC2) studies have been performed, gene repression is associated with PRC2 trimethylation of H3K27 (H3K27me3). However, it is uncertain whether PCR2 writing of H3K27me3 is mechanistically required for gene silencing. Here we studied PRC2 function in postnatal mouse cardiomyocytes, where the paucity of cell division obviates bulk H3K27me3 rewriting after each cell cycle. EED (Embryonic Ectoderm Development) inactivation in the postnatal heart (EedCKO) caused lethal dilated cardiomyopathy. Surprisingly, gene upregulation in EedCKO was not coupled with loss of H3K27me3. Rather, the activating histone mark H3K27ac increased. EED interacted with histone deacetylases (HDACs) and enhanced their catalytic activity. HDAC overexpression normalized EedCKO heart function and expression of derepressed genes. Our results uncovered a non-canonical, H3K27me3-independent EED repressive mechanism that is essential for normal heart function. Our results further illustrate that organ dysfunction due to epigenetic dysregulation can be corrected by epigenetic rewiring.

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Author details

  1. Shanshan Ai

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Yong Peng

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Chen Li

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Fei Gu

    Department of Cardiology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Xianhong Yu

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Yanzhu Yue

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Qing Ma

    Department of Cardiology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jinghai Chen

    Department of Cardiology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Zhiqiang Lin

    Department of Cardiology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Pingzhu Zhou

    Department of Cardiology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Huafeng Xie

    Division of Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Terence W Prendiville

    Department of Paediatric Cardiology, Our Lady's Children's Hospital Crumlin, Dublin, Ireland
    Competing interests
    The authors declare that no competing interests exist.
  13. Wen Zheng

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  14. Yuli Liu

    Institute of Molecular Medicine, Peking University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  15. Stuart H Orkin

    Division of Hematology/Oncology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Da-zhi Wang

    Department of Cardiology, Boston Children's Hospital, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Jia Yu

    Department of Biochemistry and Molecular Biology, Peking Union Medical College, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  18. William T Pu

    Department of Cardiology, Boston Children's Hospital, Cambridge, United States
    For correspondence
    wpu@pulab.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4551-8079
  19. Aibin He

    Institute of Molecular Medicine, Peking University, Beijing, China
    For correspondence
    ahe@pku.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3489-2305

Funding

National Natural Science Foundation of China (31571487)

  • Aibin He

National Institutes of Health (U01HL098166)

  • William T Pu

National Institutes of Health (HL095712)

  • William T Pu

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

Ethics

Animal experimentation: All animal experiments were performed according to protocols (protocol number: Lsc-HeAB-1) approved by the Institutional Animal Care and Use Committees of Peking University

Reviewing Editor

  1. Jeannie T Lee, Massachusetts General Hospital, United States

Publication history

  1. Received: December 22, 2016
  2. Accepted: April 9, 2017
  3. Accepted Manuscript published: April 10, 2017 (version 1)
  4. Version of Record published: April 21, 2017 (version 2)

Copyright

© 2017, Ai 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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