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.
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
Further reading
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- Neuroscience
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Fibro-adipogenic progenitors (FAPs) are muscle-resident mesenchymal progenitors that can contribute to muscle tissue homeostasis and regeneration, as well as postnatal maturation and lifelong maintenance of the neuromuscular system. Recently, traumatic injury to the peripheral nerve was shown to activate FAPs, suggesting that FAPs can respond to nerve injury. However, questions of how FAPs can sense the anatomically distant peripheral nerve injury and whether FAPs can directly contribute to nerve regeneration remained unanswered. Here, utilizing single-cell transcriptomics and mouse models, we discovered that a subset of FAPs expressing GDNF receptors Ret and Gfra1 can respond to peripheral nerve injury by sensing GDNF secreted by Schwann cells. Upon GDNF sensing, this subset becomes activated and expresses Bdnf. FAP-specific inactivation of Bdnf (Prrx1Cre; Bdnffl/fl) resulted in delayed nerve regeneration owing to defective remyelination, indicating that GDNF-sensing FAPs play an important role in the remyelination process during peripheral nerve regeneration. In aged mice, significantly reduced Bdnf expression in FAPs was observed upon nerve injury, suggesting the clinical relevance of FAP-derived BDNF in the age-related delays in nerve regeneration. Collectively, our study revealed the previously unidentified role of FAPs in peripheral nerve regeneration, and the molecular mechanism behind FAPs’ response to peripheral nerve injury.
