Unmasking Transcriptional Heterogeneity in Senescent Cells

By Alejandra Hernandez-Segura, Tristan de Jong, S. Melov, V. Guryev, J. Campisi, M. Demaria. Current Biology, 2017

778 citations recorded by the source corpus.

SUMMARY Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5–8], and organismal aging [9]. The senescence program is variably characterized by several non-exclusive markers, including constitutive DNA damage response (DDR) signaling, senescence-associated β-galactosidase (SA-βgal) activity, increased expression of the cyclin-dependent kinase (CDK) inhibitors p16INK4A (CDKN2A) and p21CIP1 (CDKN1A), increased secretion of many bio-active factors (the senescence-associated secretory phenotype, or SASP), and reduced expression of the nuclear lamina protein LaminB1 (LMNB1) [1]. Many senescence-associated markers result from altered transcription, but the senescent phenotype is variable, and methods for clearly identifying senescent cells are lacking [10]. Here, we characterize the heterogeneity of the senescence program using numerous whole-transcriptome datasets generated by us or publicly available. We identify transcriptome signatures associated with specific senescence-inducing stresses or senescent cell types and identify and validate genes that are commonly differentially regulated. We also show that the senescent phenotype is dynamic, changing at varying intervals after senescence induction. Identifying novel transcriptome signatures to detect any type of senescent cell or to discriminate among diverse senescence programs is an attractive strategy for determining the diverse biological roles of senescent cells and developing specific drug targets.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e2255d82289fb291aa81913ed4cb5f95bf6d8aa1

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Citations in the corpus

Single-Cell Transcriptomic Analysis of Human Lung Provides Insights into the Pathobiology of Pulmonary Fibrosis (2019, methodology): “Therefore, we used the expression of 1,311 replicative senescence-associated genes to generate a senescence score for any individual cell and applied it to epithelial cells in our dataset (Figure 9B, see Figure 6 for a description of the clusters) (46).”
Immunosenescence: molecular mechanisms and diseases (2023, background): “Senescence is not an acute transition but is progressive and phased from a temporary or reversible state to a chronic irreversible state.(163,194) Simple anti-senescence may not produce the expected therapeutic effects and can harm healthy tissues in elderly individuals.”
The senescence-associated secretory phenotype and its physiological and pathological implications (2024, neutral): “It was also demonstrated that the production of SASP proteins follows the upregulation of their mRNAs, thus allowing the use of qPCR and later RNA sequencing for SASP identification 11,21 .”
A proteomic atlas of senescence-associated secretomes for aging biomarker development (2019, methodology): “Transcriptome analysis of IR- and RAS-induced senescent fibroblasts were obtained from published studies [24,44] and combined.”
Hallmarks of Cellular Senescence. (2018, neutral): “It is clear that the SASP has an important role in the pathophysiological activity of senescent cells, but it is too unspecific and heterogeneous to be used as an unequivocal marker for senescence [49,52].”