Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation

Abstract
Data availability
Article and author information

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

1. Kim J et al
(2018) Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation
NCBI Gene Expression Omnibus, GSE112606.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112606

The following previously published data sets were used

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NCBI Gene Expression Omnibus, GSE55709.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE55709
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NCBI Gene Expression Omnibus, GSE66081.

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NCBI Gene Expression Omnibus, GSE61852.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE61852
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NCBI Gene Expression Omnibus, GSE69669.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69669
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NCBI Gene Expression Omnibus, GSE86897.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE86897
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https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE79320

Article and author information

Author details

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.
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.
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.
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.
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.
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.
Davide Seruggia

Pediatric Oncology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
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.
Stuart H Orkin

Pediatric Oncology, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.