Novel insights from a multiomics dissection of the hayflick limit
- Calico Life Sciences, LLC, United States
- Calico Life Sciences LLC, United States
Abstract
The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflick’s original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by the transcription factors YAP1/TEAD1 and TGF-𝛽2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.
Data availability
Sequencing data have been deposited in GEO under accession code GSE175533.Proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository under accession code EBI PRIDECode for processing and analyzing data modalities have been deposited at https://github.com/dghendrickson/hayflickSource data for figures and analysis have been deposited at https://github.com/dghendrickson/hayflick and/or uploaded as source data files.
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Transcriptome analysis of oxdative-stress induced senescence in human astrocytesNCBI Gene Expression Omnibus, GSE58910.
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Mapping of nucleolus-associated chromosomal domains during replicative senescence.NCBI Gene Expression Omnibus, GSE78043.
Article and author information
Author details
Jonathon J O'Brien
David G Hendrickson
Funding
The authors are employed by Calico Sciences, and no external funding was received.
Copyright
© 2022, Chan 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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Novel insights from a multiomics dissection of the hayflick limit
eLife 11:e70283.
https://doi.org/10.7554/eLife.70283
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