Novel insights from a multiomics dissection of the Hayflick limit

• Published in: eLife Vol. 11
• Main Authors: Chan, Michelle, Yuan, Han, Soifer, Ilya, Maile, Tobias M, Wang, Rebecca Y, Ireland, Andrea, O'Brien, Jonathon J, Goudeau, Jérôme, Chan, Leanne J G, Vijay, Twaritha, Freund, Adam, Kenyon, Cynthia, Bennett, Bryson D, McAllister, Fiona E, Kelley, David R, Roy, Margaret, Cohen, Robert L, Levinson, Arthur D, Botstein, David, Hendrickson, David G
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 04-02-2022; eLife Sciences Publications, Ltd
• Subjects: Aged; Aging; Aging - physiology; Cell culture; Cell cycle; Cell Line; Cellular Senescence - genetics; Chromosomes and Gene Expression; Epigenetics; epithelial to mesenchymal transition; Epithelial-Mesenchymal Transition; Experiments; Fibroblasts; Fibroblasts - metabolism; Gene expression; Generalized linear models; Genetics and Genomics; Genotype & phenotype; Humans; Mesenchyme; Metabolism; Metabolomics; myofibroblast; Nucleoli; Osteoporosis; Proteins; Proteomics; Pulmonary fibrosis; Radiation; replicative senescence; Senescence; Telomerase; Yes-associated protein; replicative senescence; genetics; myofibroblast; chromosomes; epithelial to mesenchymal transition; genomics; human; gene expression
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.70283

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 t 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.