Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment

  1. Mélanie Criqui
  2. Aditi Qamra
  3. Tsz Wai Chu
  4. Monika Sharma
  5. Julissa Tsao
  6. Danielle A Henry
  7. Dalia Barsyte-Lovejoy
  8. Cheryl H Arrowsmith
  9. Neil Winegarden
  10. Mathieu Lupien
  11. Lea Harrington  Is a corresponding author
  1. University of Montreal, Canada
  2. University Health Network, Canada
  3. McGill University Health Centre, Canada
  4. University of Toronto, Canada
  5. University Heath Network, Canada

Abstract

The precise relationship between epigenetic perturbations and telomere dysfunction is an extant question. Previously, we showed that telomere dysfunction leads to differentiation instability in murine embryonic stem cells (mESCs) via perturbations in DNA methylation at pluripotency-factor promoters. Here, we uncovered that telomerase reverse transcriptase null (Tert-/-) mESCs exhibit genome-wide perturbations in chromatin accessibility and gene expression during differentiation. These changes were accompanied by an increase of H3K27me3 globally, an altered chromatin landscape at the Pou5f1/Oct4 pluripotency gene promoter, and impaired Tert-/- mESC differentiation. Inhibition of the Polycomb Repressive Complex 2 (PRC2), an H3K27 tri-methyltransferase, exacerbated the impairment in differentiation and pluripotency gene repression in Tert-/- mESCs but not wild-type mESCs, whereas inhibition of H3K27me3 demethylation led to a partial rescue of the Tert-/- phenotype. This data reveals a new interdependent relationship between H3K27me3 and telomere integrity in stem cell lineage commitment that may have implications in aging and cancer.

Data availability

ATAC-seq and ChIP-seq data has been deposited in GEO under accession number GSE130780 and GSE146322. The Metadata sheet accompanying this deposition is provided in Figure 4 - source data files 2 and 4.

The following data sets were generated

Article and author information

Author details

  1. Mélanie Criqui

    Department of Molecular Biology, University of Montreal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  2. Aditi Qamra

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Tsz Wai Chu

    Clinical Research Unit, McGill University Health Centre, Montréal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Monika Sharma

    Princess Margaret Genomics Centre, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  5. Julissa Tsao

    Princess Margaret Genomics Centre, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  6. Danielle A Henry

    Department of Molecular Biology, University of Montreal, Montreal, Canada
    Competing interests
    The authors declare that no competing interests exist.
  7. Dalia Barsyte-Lovejoy

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  8. Cheryl H Arrowsmith

    Structural Genomics Consortium, University of Toronto, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  9. Neil Winegarden

    Princess Margaret Genomics Centre, University Heath Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
  10. Mathieu Lupien

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0929-9478
  11. Lea Harrington

    Department of Medicine, University of Montreal, Montreal, Canada
    For correspondence
    lea.harrington@umontreal.ca
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4977-2744

Funding

Canadian Institutes of Health Research (367427)

  • Lea Harrington

Canadian Institutes of Health Research (133573)

  • Lea Harrington

Wellcome (084637)

  • Lea Harrington

Ontario Genomics Institute (OGI-055)

  • Cheryl H Arrowsmith

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

Reviewing Editor

  1. Raymund Wellinger, Université de Sherbrooke, Canada

Publication history

  1. Received: April 2, 2019
  2. Accepted: April 6, 2020
  3. Accepted Manuscript published: April 16, 2020 (version 1)
  4. Version of Record published: April 30, 2020 (version 2)

Copyright

© 2020, Criqui 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. Mélanie Criqui
  2. Aditi Qamra
  3. Tsz Wai Chu
  4. Monika Sharma
  5. Julissa Tsao
  6. Danielle A Henry
  7. Dalia Barsyte-Lovejoy
  8. Cheryl H Arrowsmith
  9. Neil Winegarden
  10. Mathieu Lupien
  11. Lea Harrington
(2020)
Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment
eLife 9:e47333.
https://doi.org/10.7554/eLife.47333
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