Arp2/3 complex activity enables nuclear YAP for naïve pluripotency of human embryonic stem cells
- University of California, San Francisco, United States
Abstract
Our understanding of the transitions of human embryonic stem cells between distinct stages of pluripotency relies predominantly on regulation by transcriptional and epigenetic programs with limited insight on the role of established morphological changes. We report remodeling of the actin cytoskeleton of human embryonic stem cells (hESCs) as they transition from primed to naïve pluripotency which includes assembly of a ring of contractile actin filaments encapsulating colonies of naïve hESCs. Activity of the Arp2/3 complex is required for the actin ring, to establish uniform cell mechanics within naïve colonies, promote nuclear translocation of the Hippo pathway effectors YAP and TAZ, and effective transition to naïve pluripotency. RNA-sequencing analysis confirms that Arp2/3 complex activity regulates Hippo signaling in hESCs, and impaired naïve pluripotency with inhibited Arp2/3 complex activity is rescued by expressing a constitutively active, nuclear-localized YAP-S127A. Moreover, expression of YAP-S127A partially restores the actin filament fence with Arp2/3 complex inhibition, suggesting that actin filament remodeling is both upstream and downstream of YAP activity. These new findings on the cell biology of hESCs reveal a mechanism for cytoskeletal dynamics coordinating cell mechanics to regulate gene expression and facilitate transitions between pluripotency states.
Data availability
RNA sequencing data generated for this manuscript were deposited in NCBI Gene Expression Omnibus (Accession Number: GSE276968). All data generated or analyzed during this study are included in the manuscript or supporting files.
Article and author information
Author details
Funding
National Science Foundation (1933240)
- Nathaniel Paul Meyer
- Todd G Nystul
- Diane L Barber
National Cancer Institute (9938488)
- Nathaniel Paul Meyer
- Diane L Barber
National Heart, Lung, and Blood Institute (F31HL162520)
- Tania Singh
Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD055764)
- Nathaniel Paul Meyer
- Todd G Nystul
- Diane L Barber
National Institute of General Medical Sciences (GM136348)
- Nathaniel Paul Meyer
- Todd G Nystul
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2024, Meyer 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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Arp2/3 complex activity enables nuclear YAP for naïve pluripotency of human embryonic stem cells
eLife 13:e89725.
https://doi.org/10.7554/eLife.89725
