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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- Stem Cells and Regenerative Medicine
The lateral wall of the mouse subventricular zone harbors neural stem cells (NSC, B cells) which generate proliferating transient-amplifying progenitors (TAP, C cells) that ultimately give rise to neuroblasts (NB, A cells). Molecular profiling at the single-cell level struggles to distinguish these different cell types. Here, we combined transcriptome analyses of FACS-sorted cells and single-cell RNAseq to demonstrate the existence of an abundant, clonogenic and multipotent population of immature neuroblasts (iNB cells) at the transition between TAP and migrating NB (mNB). iNB are reversibly engaged in neuronal differentiation. Indeed, they keep molecular features of both undifferentiated progenitors, plasticity and unexpected regenerative properties. Strikingly, they undergo important progressive molecular switches, including changes in the expression of splicing regulators leading to their differentiation in mNB subdividing them into two subtypes, iNB1 and iNB2. Due to their plastic properties, iNB could represent a new target for regenerative therapy of brain damage.
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- Biochemistry and Chemical Biology
- Stem Cells and Regenerative Medicine
Human induced pluripotent stem cells (hiPSCs) have great potential to be used as alternatives to embryonic stem cells (hESCs) in regenerative medicine and disease modelling. In this study, we characterise the proteomes of multiple hiPSC and hESC lines derived from independent donors and find that while they express a near-identical set of proteins, they show consistent quantitative differences in the abundance of a subset of proteins. hiPSCs have increased total protein content, while maintaining a comparable cell cycle profile to hESCs, with increased abundance of cytoplasmic and mitochondrial proteins required to sustain high growth rates, including nutrient transporters and metabolic proteins. Prominent changes detected in proteins involved in mitochondrial metabolism correlated with enhanced mitochondrial potential, shown using high-resolution respirometry. hiPSCs also produced higher levels of secreted proteins, including growth factors and proteins involved in the inhibition of the immune system. The data indicate that reprogramming of fibroblasts to hiPSCs produces important differences in cytoplasmic and mitochondrial proteins compared to hESCs, with consequences affecting growth and metabolism. This study improves our understanding of the molecular differences between hiPSCs and hESCs, with implications for potential risks and benefits for their use in future disease modelling and therapeutic applications.
