TY - JOUR
T1 - A multidimensional systems biology analysis of cellular senescence in aging and disease
AU - Avelar, Roberto A.
AU - Ortega, Javier Gómez
AU - Tacutu, Robi
AU - Tyler, Eleanor J.
AU - Bennett, Dominic
AU - Binetti, Paolo
AU - Budovsky, Arie
AU - Chatsirisupachai, Kasit
AU - Johnson, Emily
AU - Murray, Alex
AU - Shields, Samuel
AU - Tejada-Martinez, Daniela
AU - Thornton, Daniel
AU - Fraifeld, Vadim E.
AU - Bishop, Cleo L.
AU - De Magalhães, João Pedro
N1 - Publisher Copyright:
© 2020 The Author(s).
PY - 2020/4/7
Y1 - 2020/4/7
N2 - 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.
AB - 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.
KW - Biogerontology
KW - Cancer
KW - Genetics
KW - Longevity
KW - Transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85083072235&partnerID=8YFLogxK
U2 - 10.1186/s13059-020-01990-9
DO - 10.1186/s13059-020-01990-9
M3 - Article
C2 - 32264951
AN - SCOPUS:85083072235
SN - 1474-7596
VL - 21
JO - Genome Biology
JF - Genome Biology
IS - 1
M1 - 91
ER -