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衰老与疾病中细胞衰老的多维系统生物学分析

A multidimensional systems biology analysis of cellular senescence in aging and disease.

作者信息

Avelar Roberto A, Ortega Javier Gómez, Tacutu Robi, Tyler Eleanor J, Bennett Dominic, Binetti Paolo, Budovsky Arie, Chatsirisupachai Kasit, Johnson Emily, Murray Alex, Shields Samuel, Tejada-Martinez Daniela, Thornton Daniel, Fraifeld Vadim E, Bishop Cleo L, de Magalhães João Pedro

机构信息

Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK.

School of Biological Sciences, Monash University, Melbourne, VIC, 3800, Australia.

出版信息

Genome Biol. 2020 Apr 7;21(1):91. doi: 10.1186/s13059-020-01990-9.

DOI:10.1186/s13059-020-01990-9
PMID:32264951
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7333371/
Abstract

BACKGROUND

Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking.

RESULTS

We develop CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological processes. Network topological parameters also reveal novel potential cellular senescence regulators. Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence.

CONCLUSIONS

Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.

摘要

背景

细胞衰老，即原本增殖的细胞进入永久性复制停滞状态，是衰老的一个标志，并且与衰老相关疾病有关。许多基因在细胞衰老中发挥作用，但对其通路仍缺乏全面的了解。

结果

我们开发了CellAge（http://genomics.senescence.info/cells），这是一个人工整理的包含279个驱动细胞衰老的人类基因的数据库，并进行了各种综合分析。诱导细胞衰老的基因在人体组织中往往随年龄增长而过度表达，并且在抗长寿基因和肿瘤抑制基因中显著富集，而抑制细胞衰老的基因则与促长寿基因和癌基因重叠。此外，细胞衰老基因在哺乳动物中高度保守，但在无脊椎动物中并非如此。我们还构建了细胞衰老蛋白-蛋白相互作用和共表达网络。网络中的簇在细胞周期和免疫过程方面显著富集。网络拓扑参数还揭示了新的潜在细胞衰老调节因子。使用小干扰RNA，我们观察到所有测试的26个候选基因至少诱导一种衰老标志物，其中13个基因（C9orf40、CDC25A、CDCA4、CKAP2、GTF3C4、HAUS4、IMMT、MCM7、MTHFD2、MYBL2、NEK2、NIPA2和TCEB3）减少细胞数量、激活p16/p21并发生类似于细胞衰老的形态变化。

结论

总体而言，我们的工作为研究细胞衰老的研究人员提供了一个基准资源，并且我们的系统生物学分析揭示了细胞衰老的新见解和基因调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/0e1deaa6d19d/13059_2020_1990_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/4fc18b039105/13059_2020_1990_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/d5d487084617/13059_2020_1990_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/666242ea28a7/13059_2020_1990_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/f2ddd5de53c8/13059_2020_1990_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/0e1deaa6d19d/13059_2020_1990_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/4fc18b039105/13059_2020_1990_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/d5d487084617/13059_2020_1990_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/666242ea28a7/13059_2020_1990_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/f2ddd5de53c8/13059_2020_1990_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e2c/7333371/0e1deaa6d19d/13059_2020_1990_Fig5_HTML.jpg

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