Abstract
BackgroundCellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. However, the prevalence of senescent cells in healthy human tissues and the global SnG expression signature in different cell types are poorly understood.MethodsThis study performed an integrative gene network analysis of bulk and single-cell RNA-seq data in non-diseased human tissues to investigate SnG co-expression signatures and their cell-type specificity.ResultsThrough a comprehensive transcriptomic network analysis of 50 human tissues in the Genotype-Tissue Expression Project (GTEx) cohort, we identified SnG-enriched gene modules, characterized SnG co-expression patterns, and constructed aggregated SnG networks across primary tissues of the human body. Our network approaches identified 51 SnGs highly conserved across the human tissues, including CDKN1A (p21)-centered regulators that control cell cycle progression and the senescence-associated secretory phenotype (SASP). The SnG-enriched modules showed remarkable cell-type specificity, especially in fibroblasts, endothelial cells, and immune cells. Further analyses of single-cell RNA-seq and spatial transcriptomic data independently validated the cell-type specific SnG signatures predicted by the network analysis.ConclusionsThis study systematically revealed the co-regulated organizations and cell type specificity of SnGs in major human tissues, which can serve as a blueprint for future studies to map senescent cells and their cellular interactions in human tissues.
Highlights
Cellular senescence is a complex stress response that impacts cellular function and organismal health
The co-expression networks of senescence genes (SnGs) in 50 human tissues To investigate senescence gene signatures in various human tissues and cell types, we developed a network biology based framework to integrate bulk and scRNA-seq data (Fig. 1a)
We identified 125 network modules with significant enrichment (multiple-testing corrected Fisher’s exact test (FET) p-value < 0.05) of the CellAge SnGs (Fig. 1b, Table S1)
Summary
Cellular senescence is a complex stress response that impacts cellular function and organismal health. Multiple developmental and environmental factors, such as intrinsic cellular cues, radiation, oxidative stress, oncogenes, and protein accumulation, activate genes and pathways that can lead to senescence. Enormous efforts have been made to identify and characterize senescence genes (SnGs) in stress and disease systems. Cellular senescence is a complex stress response associated with four inter-dependent hallmarks: cell-cycle withdrawal, macromolecular damage, secretory phenotype, and deregulated metabolism [1]. Subsequent studies demonstrated that cells could prematurely enter senescence when exposed to adverse stimuli, including radiation, oxidative stress, telomere attrition, and oncogene signaling [3]. The accumulation of senescent cells may lead to various human diseases, including pulmonary fibrosis, hepatic steatosis, diabetes, and neurodegenerative diseases [7,8,9,10]. As senescence is closely associated with human diseases from multiple organs, the removal of senescent cells has been proposed to improve senescence-associated pathologies [11, 12]
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