Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation

  1. Lucy LeBlanc
  2. Bum-Kyu Lee
  3. Andy C Yu
  4. Mijeong Kim
  5. Aparna V Kambhampati
  6. Shannon M Dupont
  7. Davide Seruggia
  8. Byoung U Ryu
  9. Stuart H Orkin
  10. Jonghwan Kim  Is a corresponding author
  1. The University of Texas at Austin, United States
  2. Harvard Medical School, United States

Abstract

Approximately 30% of embryonic stem cells (ESCs) die after exiting self-renewal, but regulators of this process are not well known. Yap1 is a Hippo pathway transcriptional effector that plays numerous roles in development and cancer. However, its functions in ESC differentiation remain poorly characterized. We first reveal that ESCs lacking Yap1 experience massive cell death upon the exit from self-renewal. We subsequently show that Yap1 contextually protects differentiating, but not self-renewing, ESC from hyperactivation of the apoptotic cascade. Mechanistically, Yap1 strongly activates anti-apoptotic genes via cis-regulatory elements while mildly suppressing pro-apoptotic genes, which moderates the level of mitochondrial priming that occurs during differentiation. Individually modulating the expression of single apoptosis-related genes targeted by Yap1 is sufficient to augment or hinder survival during differentiation. Our demonstration of the context-dependent pro-survival functions of Yap1 during ESC differentiation contributes to our understanding of the balance between survival and death during cell fate changes.

Data availability

Sequencing data have been deposited in GEO under accession code GSE112606.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Lucy LeBlanc

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Bum-Kyu Lee

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Andy C Yu

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Mijeong Kim

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Aparna V Kambhampati

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Shannon M Dupont

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Davide Seruggia

    Pediatric Oncology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Byoung U Ryu

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Stuart H Orkin

    Pediatric Oncology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jonghwan Kim

    Department of Molecular Biosciences, The University of Texas at Austin, Austin, United States
    For correspondence
    jonghwankim@mail.utexas.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9919-9843

Funding

National Institute of General Medical Sciences (R01GM112722)

  • Jonghwan Kim

Burroughs Wellcome Fund

  • Jonghwan Kim

National Science Foundation GRFP

  • Lucy LeBlanc

Hamilton Seed Grant

  • Lucy LeBlanc

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

Reviewing Editor

  1. Marianne E Bronner, California Institute of Technology, United States

Publication history

  1. Received: July 17, 2018
  2. Accepted: December 17, 2018
  3. Accepted Manuscript published: December 18, 2018 (version 1)
  4. Version of Record published: December 27, 2018 (version 2)

Copyright

© 2018, LeBlanc 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. Lucy LeBlanc
  2. Bum-Kyu Lee
  3. Andy C Yu
  4. Mijeong Kim
  5. Aparna V Kambhampati
  6. Shannon M Dupont
  7. Davide Seruggia
  8. Byoung U Ryu
  9. Stuart H Orkin
  10. Jonghwan Kim
(2018)
Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation
eLife 7:e40167.
https://doi.org/10.7554/eLife.40167

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