Journal Article

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

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

2020

Overview

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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Aging / Aging - genetics / Animal Genetics and Genomics / Animals / Biogerontology / Bioinformatics / Biomedical and Life Sciences / Cancer / Cell cycle / Cell growth / Cell number / cell senescence / Cellular Senescence - genetics / Databases, Genetic / Deoxyribonucleic acid / Disease - genetics / DNA / DNA damage / DNA methylation / Evolution, Molecular / Evolutionary Biology / Gene Expression / Genes / Genes, Neoplasm / Genetic engineering / Genetics / Genomics / Human Genetics / Humans / Invertebrates / Kinases / Life Sciences / Longevity / Longevity - genetics / Mammals / Metabolism / Metabolites / Microbial Genetics and Genomics / Oligonucleotide Array Sequence Analysis / oncogenes / Organ Specificity / Plant Genetics and Genomics / Protein interaction / Protein Interaction Mapping / protein-protein interactions / Proteins / Regulation / RNA-Seq / Senescence / Signal transduction / siRNA / Systems Biology / topology / Transcriptome / Tumor suppressor genes