Novel insights from a multiomics dissection of the Hayflick limit.
Novel insights from a multiomics dissection of the Hayflick limit.
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DOI：
10.7554/elife.70283
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发表时间：
2022-02-04
期刊：
影响因子：
7.7
通讯作者：
Hendrickson DG
中科院分区：
文献类型：
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作者：
Chan M;Yuan H;Soifer I;Maile TM;Wang RY;Ireland A;O'Brien JJ;Goudeau J;Chan LJG;Vijay T;Freund A;Kenyon C;Bennett BD;McAllister FE;Kelley DR;Roy M;Cohen RL;Levinson AD;Botstein D;Hendrickson DG
其中分裂细胞耗尽增殖能力并进入复制性衰老的过程已成为体外细胞衰老的重要模型。尽管经过数十年的研究，这种细胞状态在文化中并没有完全理解，在衰老过程中更是如此。在这里，我们回顾了伦纳德海弗利克的原始观察复制衰老的WI-38人肺成纤维细胞配备了一系列现代技术，包括RNA测序，单细胞RNA测序，蛋白质组学，代谢组学，和ATAC-seq。我们发现的证据表明，到衰老状态的过渡体现早期，逐渐增加，并对应于一个随之而来的全球性的增加，在核仁和核纤层蛋白相关领域的DNA可及性。此外，我们证明，衰老的WI-38细胞获得一个惊人的相似之处，肌成纤维细胞在一个类似的上皮间充质转化（EMT）的过程中，由tYAP 1/TEAD 1和TGF-β2的调节。最后，我们发现维替泊芬抑制老年WI-38细胞中的YAP 1/TEAD 1活性强烈减弱了该基因表达程序。
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.