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Novel insights from a multiomics dissection of the Hayflick limit.

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 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.

SUBMITTER: Chan M

PROVIDER: S-EPMC8933007 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Novel insights from a multiomics dissection of the Hayflick limit.

Chan Michelle M Yuan Han H Soifer Ilya I Maile Tobias M TM Wang Rebecca Y RY Ireland Andrea A O'Brien Jonathon J JJ Goudeau Jérôme J Chan Leanne J G LJG Vijay Twaritha T Freund Adam A Kenyon Cynthia C Bennett Bryson D BD McAllister Fiona E FE Kelley David R DR Roy Margaret M Cohen Robert L RL Levinson Arthur D AD Botstein David D Hendrickson David G DG

eLife 20220204

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, metabolom ...[more]

PMID: 35119359

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Project description:IntroductionBody mass index (BMI) is considered an important factor in tumor prognosis, but its role in gastric cancer (GC) remains controversial. There is a lack of studies exploring the effect of BMI on gastric cancer from the perspective of intratumoral microbiota. This study aimed to compare and analyze the differences in and functions of intratumoral microbiota among GC patients with varying BMIs, aiming to ascertain whether specific microbial features are associated with prognosis in low-BMI (LBMI) gastric cancer patients.MethodsA retrospective analysis of the clinicopathological features and prognosis of 5567 patients with different BMIs was performed between January 2010 and December 2019. Tumor tissues from 189 GC patients were collected for 16S rRNA sequencing, 64 samples were selected for transcriptome sequencing, and 57 samples were selected for untargeted metabolomic analysis.ResultsClinical cohort analysis revealed that GC patients with a low BMI presented poorer clinical and pathological characteristics than those with a non-low-BMI (NLBMI). LBMI was identified as a significant independent risk factor for adverse prognosis, potentially exerting immunosuppressive effects on postoperative adjuvant chemotherapy. 16S rRNA sequencing revealed no significant differences in the alpha and beta diversity of the intratumoral microbiota between the two groups of GC patients. However, LEfSe analysis revealed 32 differential intratumoral microbiota between the LBMI and NLBMI groups. Notably, the genus Abiotrophia was significantly enriched in the LBMI group. Further in-depth analysis indicated that the genus Abiotrophia was inversely associated with eosinophils, P2RY12, and SCN4B genes, and positively linked with LGR6 in LBMI gastric cancer patients. Metabolomic assessments revealed that LBMI was positively associated with purine metabolites, specifically guanine and inosine diphosphate (IDP).DiscussionIn conclusion, LBMI is an independent risk factor for poor prognosis in gastric cancer patients and may have an inhibitory effect on postoperative adjuvant chemotherapy. Intratumor flora of gastric cancer patients with different BMI levels differed, with different immune cell infiltration and metabolic characteristics. The genus Abiotrophia may promote gastric cancer development and progression by regulating eosinophils and the purine metabolism pathway, which provides a new idea for the precise treatment of gastric cancer.

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Novel insights from a multiomics dissection of the Hayflick limit.

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Novel insights from a multiomics dissection of the Hayflick limit.

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