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

Genome Biology - 2020
Roberto A. Avelar1, Javier Gómez Ortega1, Robi Tăcutu1, Eleanor J. Tyler2, Dominic Bennett1, Paolo Binetti1, Arie Budovsky3, Kasit Chatsirisupachai1, Emily Johnson1, Alex Murray1, Samuel Shields1, Daniela Tejada‐Martinez1, Daniel Thornton1, Vadim E. Fraifeld4, Cleo L. Bishop2, João Pedro de Magalhães1
1Integrative Genomics of Ageing Group, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, L7 8TX, UK
2Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 2AT, UK
3Research and Development Authority, Barzilai Medical Center, Ashkelon, Israel
4The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Center for Multidisciplinary Research on Aging, Ben-Gurion University of the Negev, 8410501, Beer Sheva, Israel

Tóm tắt

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.

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