Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation
- The University of Texas at Austin, United States
- 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.
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Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiationNCBI Gene Expression Omnibus, GSE112606.
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Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth.NCBI Gene Expression Omnibus, GSE66081.
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YAP1 Exerts Its Transcriptional Control via TEAD-Mediated Activation of Enhancers.NCBI Gene Expression Omnibus, GSE61852.
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Superenhancer reprogramming drives a B-cell-epithelial transition and high-risk leukemia.NCBI Gene Expression Omnibus, GSE86897.
Article and author information
Author details
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
- Marianne E Bronner, California Institute of Technology, United States
Version history
- Received: July 17, 2018
- Accepted: December 17, 2018
- Accepted Manuscript published: December 18, 2018 (version 1)
- 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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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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